Débora Marques de Miranda

The leukocytes expressing DARPP-32 are reduced in patients with schizophrenia and bipolar disorder

Bipolar disorder (BPD) and schizophrenia (SCZ) are severe disorders representing an enormous social, familiar and individual burden, being SCZ the most disabling psychiatric disorder characterized by psychosis and cognitive impairment. It is well known that SCZ and BPD are associated with abnormalities in dopamine signaling pathway. Recent data in the literature have demonstrated altered expression levels of some proteins involved in the modulation of this pathway in both brain and peripheral tissues. It was shown that protein and mRNA levels of dopamine and cAMP regulated phosphoprotein (DARPP-32) were downregulated in dorsolateral prefrontal cortex (DLPFC) of patients with SCZ or BPD when compared to controls. Due to the difficulty to access brain tissue and the absence of objective laboratory tests for bio-markers, we measured DARPP-32 expression in blood cell sub-populations (CD4+ T lymphocytes, CD56+ NK cells, CD19+ B lymphocytes and CD14+ monocytes) taking advantage of the close relation of nervous and immune systems. Using flow cytometry as the analytical method, our results have shown that the DARPP-32 expression was diminished in CD4+ T lymphocytes, CD19+ B lymphocytes and CD14+ monocytes of BPD patients and was also decreased in CD4+ T lymphocytes and CD56+ NK cells of SCZ patients. These results showed that DARPP-32 expression in immune cells agrees with reports of reduced DARPP-32 protein in the DLPFC of BPD or SCZ patients. Our data suggest that DARPP-32 expression in PBMC could be used as a source of bio-markers to help in the treatment response of neuropsychiatry disorders as a window to the changes in the brain of those patients.

An association study between the Val66Met polymorphism of the BDNF gene and postpartum depression

Postpartum depression disorder (PPD) is a severe illness affecting around 15% of deliveries. Several evidences suggest that PPD is, at least, partially genetic determined. The gene encoding BDNF is a strong candidate for pathogenesis of PPD since that it has been observed decrease of serum BDNF in patients suffering from PPD. The gene encoding BDNF has a polymorphism (Val66Met) that alters the regulated protein secretion; the methionine variant being associated with insufficient secretion compared with the Valine variant. We hypothesized that BDNF gene Val66Met polymorphism could be associated with PPD. We assessed 227 subjects randomly selected who had delivery at a maternity hospital using EPDS. Differences in genotype frequency were calculated by χ2 test. Logistic Regression Analyses was performed to verify the existence of interaction between biological, psychiatric and environmental variables and PPD. Difference between groups was tested with Student’s t test. Tests were two-tailed and results significant when p ≤ 0.05. No difference in BDNF genotype distribution was observed between the depressed and non-depressed women. Educational level, stress during pregnancy, bipolar disorder and anxiety was strongly associated with PPD. We were not able to show an association between BDNF polymorphisms and PPD. Further studies are necessary to both of confirm our results and improve validity of PPD diagnosis.

The role of 5-HTTLPR polymorphism in antidepressant-associated mania in bipolar disorder

BACKGROUND The occurrence of mania during antidepressant treatment is a key issue in the clinical management of bipolar disorder (BD). The serotonin transporter gene is a candidate to be associated with antidepressant-associated mania (AAM) in some patients. This gene has a polymorphism within the promoter region (5-HTTLPR) with two allelic forms, the long (L) and the short (S) variants. METHODS We performed a case-control study to compare 5-HTTLPR genotype and allelic frequencies between 43 patients with a DSM-IV diagnosis of BD, with at least one manic/hypomanic episode associated with treatment with proserotonergic antidepressants (AAM+) and 69 unrelated, matched bipolar patients, who had been exposed to proserotonergic antidepressants without development of manic symptoms (AAM-(*)). Furthermore, we performed this comparison between a subgroup of 23 AAM+ patients that, when they presented AAM, were not using mood stabilizer (AAM+(*)) and 25 AAM- patients who used antidepressant without the concomitant use of a mood stabilizer (AAM-(*)). 5-HTTLPR genotyping was performed using PCR. RESULTS No significant differences were found between AAM+ and AAM-. Within the subgroups, our results show that S-carriers (LS+SS Genotypes) are more prone to make a manic/hypomanic episode associated with antidepressant (P=0.017). LIMITATIONS Our study is retrospective. CONCLUSIONS The 5-HTTLPR polymorphism may be considered a predictor of abnormal response to antidepressant in patients with BP, but this action is influenced by the presence of a mood stabilizer. Such observations reinforce that a correct diagnosis of bipolarity before the beginning of the treatment is essential, mainly for S-carriers patients.

Novel mutations of the BSCL2 and AGPAT2 genes in 10 families with Berardinelli–Seip congenital generalized lipodystrophy syndrome

Context  Congenital generalized lipodystrophy, or Berardinelli–Seip syndrome, is a rare autosomal recessive disease caused by mutations in either the BSCL2 or AGPAT2 genes. This syndrome is characterized by an almost complete loss of adipose tissue usually diagnosed at birth or early infancy resulting in apparent muscle hypertrophy. Common clinical features are acanthosis nigricans, hepatomegaly with or without splenomegaly and high stature. Acromegaloid features, cardiomyopathy and mental retardation can also be present.

Familial suicide behaviour: association with probands suicide attempt characteristics and 5‐HTTLPR polymorphism

Objective:  There is compelling evidence that a serotonergic dysfunction may play a major role in suicide behaviour and it has also been demonstrated that suicide is, at least partially, genetically determined. Thus, the serotonin‐related genes are the major candidates. Previously a functional polymorphism in the promoter region of the serotonin transporter gene (5‐HTTLPR) was identified and the presence of the short allele (S) was found to be associated with a lower level of expression of the gene and lower levels of 5‐HT uptake when compared with the long allele (L).The purpose of this study was to evaluate the association between family suicide behaviour history and probands’ suicide attempt (SA) history, SA characteristics and 5‐HTTLPR genotype.

The role of BDNF genetic polymorphisms in bipolar disorder with psychiatric comorbidities

BACKGROUND Bipolar disorder (BD) is a complex disorder where genetic factors play a major role in its etiology. Probably, no other axis I diagnosis has a co-morbidity prevalence as high as BD. Since BDNF is involved in different ways in various psychiatric disorders we hypothesized that its genetic polymorphisms could be associated with the co-morbidity phenomenon in BD. METHODS We studied 320 subjects (160 BD patients and 160 healthy controls). Genotyping was performed using made-to-order TaqMan genotyping assays (rs4923463, rs6265, rs2049045, and rs7103411). Statistical analyses were performed using UNPHASED version 3.0.12 and Haploview 4.1. RESULTS No genotypic, allelic or haplotype differences were found between bipolar patients and healthy controls. Concerning exclusively the rs4923463 (G/G) there was a significant association with alcoholism (p=0.009), smoking (p=0.006) and violent suicide attempt (p=0.03). We further found that the G-G haplotype (rs4923463-rs2049045) (adjusted p=0.029) and the G-T haplotype (rs4923463-rs7103411) (adjusted p=0.029) were significantly more frequent in the group with alcoholism co-morbidity when compared with the group without this co-morbidity. LIMITATIONS Sample size and retrospective assessment of suicide behavior and psychiatric comorbidities. CONCLUSIONS The results obtained in our study indicate that BDNF variants may confer susceptibility to additional psychiatric diagnosis in BD.

Analysis of telomere attrition in bipolar disorder

BACKGROUND Telomeres can be considered a marker of biological aging. Studies have suggested that telomere shortening may be associated with aging related diseases and also psychiatric disorders. OBJECTIVES Investigate whether bipolar disorder (BD) and its clinical specificities are associated with telomere shortening. METHODS Eighty-five BD patients and 95 healthy controls were paired for age, sex and educational level. Volunteers were submitted to a psychiatric interview and clinical evaluation. Patients and controls were compared as a whole sample and within specific telomere range (short and long telomeres). Intrapatients group comparison involved type of BD and comorbidities. A Real Time Quantitative PCR was performed in order to verify leukocytes telomere length. RESULTS Bipolar disorder patients presented shorter telomeres when compared to controls (p<0.001). However, there was no significant difference in telomere length between different BD subtypes. When two groups of patients (long and short telomeres) were compared, only panic disorder showed an association with telomere categories (χ(2)=6.91; p=0.009; OR=4.27). LIMITATIONS It was not possible to collect information about time since diagnosis, which limited conclusions regarding BD chronicity and telomere length. Furthermore, medication interference upon telomere length was not controlled. CONCLUSIONS Results suggest that BD is associated with reduced telomere length. Also, panic comorbidity may represent an additive risk factor. Understanding aspects that contribute to determination of telomere size in bipolar patients allows us to understand what the impact on telomeres size is, which is a health vulnerability marker.

Expression of neuronal calcium sensor-1 (NCS-1) is decreased in leukocytes of schizophrenia and bipolar disorder patients

Schizophrenia (SCZ) and bipolar disorder (BPD) are severe illnesses representing an enormous social, familiar and individual burden that affect 1% of the population world-wide. Several evidences indicate abnormalities of the dopamine system in both SCZ and BPD. Neuronal calcium sensor-1 (NCS-1) is a protein that has many functions in neurotransmission such as inhibition of dopamine D(2) receptor desensitization, regulation of ionic channels and enhancement of exocytosis of neurotransmitters. In addition, NCS-1 protein expression and mRNA levels were found increased in pre-frontal cortex (PFC) of SCZ and BPD patients. NCS-1 expression in neural and neuroendocrine cells is well documented and, recently, it was shown that NCS-1 is also expressed in mast cells and neutrophils. NCS-1 has important functions in mast cells since it stimulates Fc epsilon RI-triggered exocytosis and the release of arachidonic acid metabolites. Then, due to the known close relation between the nervous and immune systems, we sought to investigate the NCS-1 expression in lymphocytes and monocytes (CD4+ T lymphocytes, CD56+ NK cells, CD19+ B lymphocytes and CD14+ monocytes) of SCZ and BPD patients. Using flow cytometry, our results have shown that NCS-1 expression was diminished in CD4+T lymphocytes, CD19+ B lymphocytes and CD14+ monocytes of BPD patients and also decreased in CD4+ T lymphocytes and CD56+ NK cells of SCZ patients. Results suggest that immune cells might be a cellular model for studies with SCZ and BPD patients considering NCS-1 functions. Efforts need to be done to investigate the motive of the decreased percentage of immune cells expressing NCS-1 in patients with SCZ and BPD.

Clonal composition of human adamantinomatous craniopharyngiomas and somatic mutation analyses of the patched (PTCH), Gsα and Gi2α genes

Craniopharyngioma is the most common childhood tumor and thought to arise from embryonic remnants of Rathkes pouch. The paucity of published data on the molecular basis of these tumors prompted us to examine 22 adamantinomatous craniopharyngiomas looking for genetic abnormalities. Using the X-linked polymorphic androgen receptor gene as a tool for X-chromosome inactivating analysis, we found that a subset of craniopharyngiomas are monoclonal and therefore are probably due to acquired somatic genetic defects. Thus, we investigated these tumours for mutations within three candidate genes, Gsα, Gi2α and patched (PTCH). Using single stranded conformational polymorphism (SSCP), denaturing gradient gel electrophoresis and direct sequencing, the presence of somatic mutations in these genes could not be demonstrated in any tumor. Our data indicate that a subset of craniopharyngiomas are monoclonal and the mutations in the PTCH, Gsα, and Gi2α contribute little if any to cranipharyngioma development.

Homozygosity for the +674C>T polymorphism on VEGF gene is associated with age-related macular degeneration in a Brazilian cohort

PurposeTo investigate the association between VEGF gene polymorphism and age-related macular degeneration (AMD) in a Brazilian cohort.MethodsWe examined 160 affected individuals and 140 sex- and age-matched controls recruited at the Vision Institute and the Retina Department, São Geraldo Hospital, Minas Gerais Federal University, Brazil, between 2007 and 2011. Genotyping for the VEGF rs1413711 single nucleotide polymorphism (SNP) (+674C>T) was performed. The incidence rate ratios and 95% confidence interval (CI) for AMD for this genotype was calculated. The odds ratio (OR) was also assessed by using logistic regression, controlling for CFH and LOC387715 risk genotype.ResultsWe observed a prevalence of homozygosity (TT genotype) of 18.1% for rs1413711 among AMD cases compared with 5.8% among controls (P < 0.002). The ORs for this polymorphism were 3.6 (95%CI 1.6–8.2) for homozygous subjects and 1.5 (95%CI 1.1–2.1, P < 0.01) if the subject had at least one risk allele. When we studied separately exudative and dry AMD groups, this polymorphism was statistically significant for both groups. Controlling for CFH and LOC387715 risk genotype the OR was 3.0 for VEGF homozygous, and the OR increases if the patient is homozygous for the three genes.ConclusionThe present data suggests that VEGF TT genotype is associated with AMD among Brazilian patients.