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| Author(s): |
Márcio Gerhardt Soeiro de Souza
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) |
| Defense date: | 2013-03-06 |
| Examining board members: |
Ricardo Alberto Moreno;
Elisa Macedo Brietzke;
Humberto Correa da Silva Filho;
Antonio Lúcio Teixeira Junior;
Homero Pinto Vallada Filho
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| Advisor: | Ricardo Alberto Moreno; Rodrigo Machado Vieira |
| Abstract | |
Bipolar I disorder (BD) is a disease whose main features include severe mood swings that cause severe impairment in global functioning and cognitive domains. Moreover, the number of mood episodes throughout patients life is also associated with deterioration in cognitive functions. In this context, it is important to study genetic markers for the cognitive dysfunction observed in BD to elucidate the physiopathology of this phenomenon. The main candidates for genetic modulation of cognition are the genes brain derived neurotrophic factor (BDNF), catechol-o-methyltransferase (COMT), apolipoprotein E (APOE) and 1-C subunit of the L-type voltage-gated calcium channel (CACNA1C). Furthermore, elevated levels of oxidative stress have been reported in BD for all types of mood episodes but no data is available on their impact on cognitive functioning of BD patients. The aim of this thesis was to investigate whether cognitive functioning of BD patients is influenced by BDNF, COMT, APOE, CACNA1C genotypes or by levels of oxidative damage to the DNA base guanosine (8-OHdG) and cytosine (5-Mec). One hundred sixteen patients (79 during mood episode and 37 euthymic) with BD type I (mania, depression or euthymia) and 97 healthy controls were submitted to neuropsychological evaluation and blood collection for DNA analysis. All subjects were genotyped for BDNF (rs6265), COMT (rs4680; rs165599), APOE (rs429358 and rs7412), CACNA1C (rs1006737), DNA levels of 8-OHdG and 5-Mec were also measured. Our results revealed that BD subjects that carried the rs4680/rs165599 Met/Met genotype had more severe cognitive dysfunction (executive function, verbal fluency, memory and intelligence) than carriers of other genotypes during manic or mixed episodes. Moreover, patients carrying the COMT rs4680 Met allele had worse performance on facial emotion recognition tests during manic and depressive episodes. BD carriers of the Met allele of CACNA1C had more severe executive dysfunction than non-carriers, regardless of manic or depressive symptoms. No effect of CACNA1C or COMT genotypes was observed in controls. The genotypes of BDNF or APOE were not associated with cognitive dysfunction in BD patients or controls. The BD group exhibited higher levels of 8-OHdG than the control group and these levels were influenced by the lifetime number of manic episodes, suggesting that hyperdopaminergic episodes may influence the oxidation of DNA bases. In summary, the genotype of COMT and CACNA1C may represent a useful tool for identifying BD subjects at risk of developing more severe cognitive dysfunction in all mood states of the disease. This evidence associating dopamine catabolism and calcium channels to degree of cognitive dysfunction in BD should be further explored by future research (AU) | |
| FAPESP's process: | 10/12286-8 - Genetic association study between single nucleotide polymorphism and cognitive performance in young bipolar I patients: Licavalgene |
| Grantee: | Márcio Gerhardt Soeiro-de-Souza |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |