Browsing by Author "Bettencourt, Andreia"
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- Apolipoprotein E isoforms and susceptibility to genetic generalized epilepsiesPublication . Chaves, João; Martins-Ferreira, Ricardo; Carvalho, Cláudia; Bettencourt, Andreia; Brás, Sandra; Chorão, Rui; Freitas, Joel; Samões, Raquel; Lopes, João; Ramalheira, João; Silva, Berta; Costa, Paulo; Martins Da Silva, António; Leal, BárbaraBackground: Apolipoprotein E (ApoE) is the main lipoprotein secreted in brain. It has a critical immunomodulatory function, influences neurotransmission and it is involved in repairing damaged neurons. ApoE e4 is an isoform of ApoE with altered function, and was previously associated with early onset epilepsy and refractoriness, both in animal models and in patients with focal epilepsies. There is a limited knowledge on ApoE’s role in Genetic Generalized Epilepsies (GGE). Aim: To determine if ApoE isoforms are risk factors for GGE development. Methods: A group of 337 GGE patients (193 F, 144 M, 33.6 ± 14.2 years) was compared with a group of 342 healthy individuals in a case-control genetic association study. ApoE genotyping was performed using PCR-RFLP. Results: The genotypic frequency of ApoE e3/e2 was lower in GGE patients relative to controls (6.5% in GGE vs. 11.7% in controls, p = 0.019, OR (95% CI) = 0.53 (0.305–0.905). No associations with other clinical data such as photosensitivity or age at disease onset were observed. Conclusion: Our results show that ApoE e3/e2 genotype may be a protective factor for GGE development. There is evidence that this genotype could be neuroprotective, preventing oxidative damage and promoting neuronal survival. Although replication studies are warranted, our data suggest that ApoE isoforms have a role in epileptogenic mechanisms regardless of the specific epileptic manifestations.
- Brain expression of inflammatory mediators in Mesial Temporal Lobe Epilepsy patientsPublication . Leal, Bárbara; Chaves, João; Carvalho, Cláudia; Rangel, Rui; Santos, Agostinho; Bettencourt, Andreia; Lopes, João; Ramalheira, João; Silva, Berta M.; da Silva, António Martins; Costa, Paulo P.Neuroinflammation may be central in epileptogenesis. In this study we analysed inflammatory reaction markers in brain tissue of Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (MTLE-HS) patients. TLR4, IL-1β and IL-10 gene expression as well as the presence of activated HLA-DR+ microglia was evaluated in 23 patients and 10 cadaveric controls. Inflammation characterized by the presence of HLA-DR+microglia and TLR4, IL-1β overexpression was evident in hippocampus and anterior temporal cortex of MTLE-HS patients. Anti-inflammatory IL-10 was also overexpressed in MTLE-HS patients. Our results show that hippocampal neuroinflammation extends beyond lesional limits, as far as the anterior temporal cortex.
- Characteristics of Neuro-Behçet's Disease in a Case-Series from a Single Centre in Northern PortugalPublication . Domingos, Joana; Ferrão, Cláudia; Ramalho, Joana; Rodrigues, Tiago; Moreira, Bruno; Santos, Ernestina; Bettencourt, Andreia; Martins da Silva, Ana; Silva, Berta; Pinho e Costa, Paulo; Vasconcelos, Carlos; Correia, JoãoIntroduction: Behçet's disease (BD) is a multisystem inflammatory disease of unknown etiology that may affect the CNS - Neuro-Behçet (NB). Our aim was to evaluate the frequency of neurological involvement and characterize a cohort of our NB patients. Methods: We retrospectively revised the clinical, laboratory and imaging data of a cohort of BD patients, followed in our hospital outpatient clinic. Results: We identified 138 BD patients. Twenty-five out of 138 had NB (15 female). Four patients presented with neurological symptoms. We identified a total of 37 attacks. Twenty-one attacks were classified as parenchymatous, four non-parenchymatous and 12 as other syndromes. Seventeen patients had CSF analysis performed (20 samples). Five samples were normal, 15 showed CSF pleocytosis. The most frequent finding on MRI performed in the acute phase was extensive lesions involving the brainstem. Two patients died due to the neurological involvement of BD. Conclusion: We found 18.1% prevalence of NB and a higher female-to-male ratio in our group than in other series. Gastrointestinal and vascular involvement was more frequent in the NB group. The fact that neurological involvement may be the first manifestation of BD with therapeutic implications and associated morbidity points out the relevance of an early diagnosis.
- Expression of Inflammation-Associated MicroRNAs in EpilepsyPublication . Leal, Bárbara; Carvalho, Cláudia; Chaves, João; Bettencourt, Andreia; Freitas, Joel; Lopes, João; Ramalheira, João; Silva, António M.; Costa, Paulo P.; Silva, Berta M.Background: Neuroinflammation appears as an important epileptogenic mechanism. MicroRNAs (miRNA) are small non-coding RNA molecules that function as post-transcriptional regulators of gene expression, controlling different biological process including immune system homeostasis and function. Evidences, both in patients and animal studies, have demonstrated an abnormal brain expression of miR-146a and miR-155 in Mesial Temporal Lobe Epilepsy (MTLE), the most refractory epilepsy type. Knowing that miR expression is very stable in biological fluids such as plasma or serum our aim was to characterize miR-146a and miR-155 expression in serum of MTLE and GGE patients. Methods: Expression levels of miR146a and RNU48 (reference gene) were quantified by Real-Time PCR in serum of 16 MTLE patients all with Hippocampal Sclerosis (6F, 8M, mean age= 44.1±11.7 years, age of onset= 13.5±10.6 years, 7 with Febrile Seizures antecedents). A group of 24 healthy individuals was used as control. Relative expression values were calculated using the 2-ΔΔCt method. Results: MTLE patients had a higher expression of miR-146a (6 fold) and miR-155 (2 fold) when compared to controls. Conclusion: Our results, although preliminary, show that miR-146a and miR-155 may be suitable biomarkers for epileptogenesis. It is thought that these miRNAs have role in fine-tuning the response to pro-inflammatory cytokines during epileptogenesis. Nevertheless its importance in epilepsy development it is yet not fully understood. The comprehension of this role may be relevant for the development of new therapeutic strategies.
- HLA and age of onset in myasthenia gravisPublication . Santos, Ernestina; Bettencourt, Andreia; da Silva, Ana Martins; Boleixa, Daniela; Lopes, Dina; Brás, Sandra; Costa, Paulo Pinho E.; Lopes, Carlos; Gonçalves, Guilherme; Leite, Maria Isabel; da Silva, Berta MartinsThe aetiology of MG is unknown, but both genetic and environmental factors are important. Over the years association of MG with Human Leucocyte Antigens (HLA) has been described in different populations. We investigated a possible association between HLA-DRB1 alleles and age of onset in MG. One hundred and fourteen MG patients (82 females) and 282 control individuals (CP) were studied. Patients were classified according to the age of onset (early-onset <50, n = 74 and late-onset ≥ 50, n = 20). Patients with thymoma (n = 20) were analyzed separately. HLA-DRB1 and HLA-B*08 genotyping was performed using PCR-SSP methodology. HLA-DRB1*03 allele was overrepresented in the global MG. When the early-onset subgroup was considered, this association became even stronger. Regarding the late-onset subgroup, the frequency of HLA-DRB1*01 allele was higher than in the CP. For the thymoma subgroup, the HLA-DRB1*10 allele frequency was significantly higher when compared to the CP. These results have shown a strong association of HLA-DRB1*03 with MG, especially for EOMG also in our population. HLA-DRB1*01 was associated to LOMG suggesting that is a susceptibility factor for this subgroup of the disease. This study confirms a different genetic background of MG subgroups regarding age of onset.
- Immunogenetic predisposing factors for mesial temporal lobe epilepsy with hippocampal sclerosisPublication . Leal, Bárbara; Chaves, João; Carvalho, Cláudia; Bettencourt, Andreia; Brito, Cláudia; Boleixa, Daniela; Freitas, Joel; Brás, Sandra; Lopes, João; Ramalheira, João; Costa, Paulo; Silva, Berta; Martins Da Silva, AntónioPurpose: Neuroinflammation appears as an important epileptogenic mechanism. Experimental and clinical studies have demonstrated an upregulation of pro-inflammatory cytokines such as IL-1β and TNF-α, in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Expression of these cytokines can be modulated by polymorphisms such as rs16944 and rs1800629, respectively, both of which have been associated with febrile seizures (FS) and MTLE-HS development. The human leukocyte antigen (HLA) system has also been implicated in diverse epileptic entities, suggesting a variable role of this system in epilepsy. Our aim was to analyse the association between immunogenetic factors and MTLE-HS development. For that rs16944 (-511 T>C, IL-1β), rs1800629 (-308 G>A, TNF-α) polymorphisms and HLA-DRB1 locus were genotyped in a Portuguese Population. Methods: We studied 196 MTLE-HS patients (108 females, 88 males, 44.7 ± 12.0 years, age of onset = 13.6 ± 10.3 years, 104 with FS antecedents) and 282 healthy controls in a case–control study. Results: The frequency of rs16944 TT genotype was higher in MTLE-HS patients compared to controls (14.9% in MTLE-HS vs. 7.7% in controls, p = 0.021, OR [95% CI] = 2.20 [1.13–4.30]). This association was independent of FS antecedents. No association was observed between rs1800629 genotypes or HLA-DRB1 alleles and MTLE-HS susceptibility. Also, no correlation was observed between the studied polymorphisms and disease age of onset. Conclusion: The rs16944 TT genotype is associated with MTLE-HS development what may be explained by the higher IL-1β levels produced by this genotype. High IL-1β levels may have neurotoxic effects or imbalance neurotransmission leading to seizures.
- Immunogenetic protective factors in Genetic Generalized EpilepsyPublication . Chaves, João; Martins-Ferreira, Ricardo; Ferreira, Ana Marta; Brás, Sandra; Carvalho, Cláudia; Bettencourt, Andreia; Samões, Raquel; Monteiro, Fábio; Freitas, Joel; Chorão, Rui; Lopes, João; Ramalheira, João; Silva, Berta; Costa, Paulo; Martins Da Silva, António; Leal, BárbaraBackground: Genetic Generalized Epilepsies (GGEs) are a heterogeneous group of syndromes characterized by generalized seizure activity that affects both hemispheres, with mainly genetic causes. Neuroinflammation has been established as an important mechanism in epileptogenesis. The ability to develop an appropriated immune response is strongly determined by immunogenetic factors. In this setting, our aim was to evaluate potential associations between GGEs and immunogenetic factors. Methods: The rs16944 (IL-1β -511 T > C) polymorphism and the HLA-DRB1 locus were genotyped in a Portuguese GGE population. Association with two clinicopathological features, photosensitivity and refractoriness, was investigated. This case-control study included 323 GGE patients (187 F, 136 M, 34.0 ± 13.9 years of age), 145 of which with JME diagnosis (88 F, 57 M, 34.1 ± 14.0 years), and 282 healthy controls (174 F, 108 M, 37.7 ± 11.6 years). Results: Decreased frequencies of the HLA-DRB1*09 and DRB1*13 alleles were observed in the GGE population. HLA-DRB1*07 frequency was increased in JME. Rs16944 allelic frequencies were similar between patients and controls. Conclusions: These results, not entirely consistent with previous reports, suggest that HLA molecules may have a complex role in epileptogenesis.
- Obstructive sleep apnoea syndrome and HLA in the North of PortugalPublication . Silva, Luís; Lopes, João; Ramalheira, João; Cunha, Daniela; Carvalho, Cláudia; Bettencourt, Andreia; Bras, Sandra; Costa, Paulo; Silva, M. Berta; Martins-da-Silva, António[ENG] Introduction. The obstructive sleep apnoea syndrome (OSAS) is a common, complex and polygenic disease with diverse aetiologies interacting to produce a single phenotype. OSAS occurs throughout the entire lifespan and familial aggregation has been suggested. Several predisposing factors, as age, gender and obesity have been described. Associations between HLA polymorphisms and sleep disorders are confirmed, in European and Non-European descendent populations. However the associations found between HLA alleles and OSAS have not been consistent and have no informative value for sleep disorder classification. Aims. To explore the genetic association of HLA with OSAS in a northern Portuguese population and to evaluate the role of obesity in the context of HLA in OSAS. Patients and methods. A cohort of 131 patients with OSAS was studied. Patients followed up in an Outpatient Sleep Clinic were assessed by clinical history, night sleep polygraphic recording, multiple sleep latency test (when necessary for differential diagnosis), laboratorial and demographic studies. A control population (CP) of 223 healthy individuals was used for comparison. HLA-DRB1 genotyping was performed using a polymerase chain reaction with sequence specific primers methodology. Results. In this cohort, the HLA-DRB1*03 allele was identified as a susceptibility factor for OSAS (24% OSAS vs. 15% CP; p = 0.025; odds ratio = 1.861; 95% CI = 1.081-3.205). No significant differences were found for other HLA-DBR1* alleles. Conclusion. HLA-DRB1*03 is a susceptibility factor for OSAS in Portuguese population. Key words. Gender. HLA-DRB1*03. Obesity. Obstructive sleep apnoea syndrome (OSAS). Risk factors. Sleep disorders.
- Refractory myasthenia gravis: Characteristics of a portuguese cohortPublication . Santos, Ernestina; Bettencourt, Andreia; Duarte, Sara; Gabriel, Denis; Oliveira, Vanessa; da Silva, Ana Martins; Costa, Paulo Pinho; Lopes, Carlos; Gonçalves, Guilherme; da Silva, Berta Martins; Leite, Maria IsabelIntroduction: Some myasthenia gravis (MG) patients are refractory to conventional treatments. Methods: To describe the clinical features of refractory MG (RMG) and explore the association with human leukocyte antigen HLA-DRB1 alleles, a cohort study of 114 consecutive MG patients was performed. Patients were classified as RMG based on predefined criteria. Results: Twenty-two patients were found to have RMG (19.3%). There were no differences between non-RMG and RMG patients with respect to sex, age of onset, abnormal 3-Hz repetitive nerve stimulation, anti-acetylcholine receptor antibody positivity, thymectomy, thymoma or thymic hyperplasia, and polyautoimmunity. HLA-DRB1*03 was more frequent in the non-RMG vs. control population (P = 3 × 10-6 ). The HLA-DRB1*13 allele was less frequent in non-RMG patients compared with controls (P = 0.002), and less frequent in the non-RMG group compared with the RMG group (P = 0.003). Discussion: HLA-DRB1*03 was more common in non-RMG, and the HLA-DRB1*13 allele appeared to have a protective role, as reported previously in other autoimmune disorders. Muscle Nerve 60: 188-191, 2019.
- Serum 25-hydroxyvitamin D levels in a healthy population from the North of PortugalPublication . Bettencourt, Andreia; Boleixa, Daniela; Reis, Júlia; Oliveira, José Carlos; Mendonça, Denisa; Costa, Paulo Pinho; Silva, Berta Martins da; Marinho, António; Silva, Ana Martins daVitamin D status in human populations has become a matter of great concern, in the wake of a multitude of published works that document widespread vitamin D deficiency across Europe, even in countries with abundant sunlight. In Portugal there are no measures of 25-hydroxyvitamin D - 25(OH)D - levels in the general adult population. The purpose of this study was to measure 25(OH)D levels in a healthy population cohort and investigate the possible association with season and selected demographic and laboratory measurements. A cohort of 198 participants (18-67 years) living in the north of Portugal, Porto, conducted in July and August 2015 (summer time) and April 2016 (winter time) was studied to evaluate serum 25(OH)D levels. Sociodemographic characteristics (age, sex and body mass index) and season of the year were taken into account as possible 25(OH)D levels codeterminants. In the whole group, the mean level of serum 25(OH)D was 55.4±23.4 nmol/L, with 48% of the population presenting levels compatible with vitamin D deficiency (below 50 nmol/L). In the winter period, this value reaches 74%. No statistically significant differences were observed between genders (57.4±23.9 vs. 53.3±22.8 nmol/L, p=0.219) as well as no statistically significant correlation was found between age and 25(OH)D levels (p=0.349). As expected higher levels of 25(OH)D were observed in summer than in winter (68.2±21.5 vs. 42.2±16.9 nmol/L; p<0.0001). Serum 25(OH)D levels were significantly lower in obese compared to non-obese subjects (46.6±17.6 vs. 57.7±24.2 nmol/L, p=0.012). Vitamin D deficiency is prevalent in this area, affecting almost half of the population. Body mass index and season are predictors for lower 25-hydroxyvitamin D levels and vitamin D status. An effective strategy to prevent vitamin D deficiency and insufficiency should be envisaged and implemented in our population.