ESTEVAO SCOTTI MUZZI MARQUES LEITAO
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- Anterior cingulate cortex neurometabolites in bipolar disorder are influenced by mood state and medication: A meta-analysis of H-1-MRS studies(2021) SCOTTI-MUZZI, Estevao; UMLA-RUNGE, Katja; SOEIRO-DE-SOUZA, Marcio GerhardtThe anterior cingulate cortex (ACC), a brain region that mediates affect and cognition by connecting the frontal cortex to limbic structures, has been consistently implicated in the neurobiology of Bipolar Disorder (BD). Proton magnetic resonance spectroscopy (H-1-MRS) studies have extensively compared in vivo neurometabolite levels of BD patients and healthy controls (HC) in the ACC. However, these studies have not been analyzed in a systematic review or meta-analysis and nor has the influence of mood state and medication on neurometabolites been examined in this cortical region. A systematic review and a meta-analysis of H-1-MRS studies comparing ACC neurometabolite profiles of adult BD patients and HC subjects was conducted, retrieving 27 articles published between 2000 and 2018. Overall increased ACC levels of Glx [glutamine (Gln) + glutamate)/Creatine], Gln, choline (Cho) and Cho/Creatine were found in BD compared to HC. Bipolar depression was associated with higher Cho levels, while euthymia correlated with higher glutamine (Gln) and Cho. Mood stabilizers appeared to affect ACC Glu and Gln metabolites. Increased ACC Cho observed in euthymia, depression and in medication-free groups could be considered a trait marker in BD and attributed to increased cell membrane phospholipid turnover. Overall increased ACC Glx was associated with elevated Gln levels, particularly influenced by euthymia, but no abnormality in Glu was detected. Further H-1-MRS studies, on other voxels, should assess more homogeneous (mood state-specific), larger BD samples and account for medication status using more sensitive H-1-MRS techniques.
- Anterior cingulate cortex neuro-metabolic changes underlying lithium-induced euthymia in bipolar depression: A longitudinal H-1-MRS study(2021) SOEIRO-DE-SOUZA, M. G.; SCOTTI-MUZZI, E.; FERNANDES, F.; SOUSA, R. T. De; LEITE, C. C.; OTADUY, M. C.; MACHADO-VIEIRA, R.The diagnosis and treatment of bipolar depression (BDep) poses complex clinical challenges for psychiatry. Proton magnetic resonance spectroscopy (H-1-MRS) is a useful imaging tool for investigating in vivo levels of brain neuro-metabolites, critical to understanding the process of mood dysregulation in Bipolar Disorder. Few studies have evaluated longitudinal clinical outcomes in BDep associated with H-1-MRS metabolic changes. This study aimed to longitudinally assess brain H-1-MRS metabolites in the anterior cingulate cortex (ACC) correlated with improvement in depression (from BDep to euthymia) after lithium treatment in BDep patients versus matched healthy controls (HC). Twenty-eight medication-free BDep patients and 28 HC, matched for age and gender, were included in this study. All subjects were submitted to a 3-Tesla brain H-1-MRS scan in the ACC using a single-voxel (8cm(3)) PRESS sequence at baseline. At follow-up (6 weeks), 14 BDep patients repeated the exam in euthymia. Patients with current BDep had higher baseline Myo-inositol/Cr (mI/Cr) and Choline/Cr (Cho/Cr) compared to HC. After six weeks, mI/Cr or Cho/Cr levels in subjects that achieved euthymia no longer differed to levels in HC, while high Cho/Cr levels persisted in non-responders . Elevated ACC mI/Cr and Cho/Cr in BDep might indicate increased abnormal membrane phospholipid metabolism and phosphatidylinositol (PI) cycle activity. Return of mI/Cr and Cho/Cr to normal levels after lithium-induced euthymia sug-gests a critical regulatory effect of lithium targeting the PI cycle involved in mood regulation.
- ACC Glu/GABA ratio is decreased in euthymic bipolar disorder I patients: possible in vivo neurometabolite explanation for mood stabilization(2021) SCOTTI-MUZZI, Estevao; CHILE, Thais; MORENO, Ricardo; PASTORELLO, Bruno Fraccini; LEITE, Claudia da Costa; HENNING, Anke; OTADUY, Maria Concepcion Garcia; VALLADA, Homero; SOEIRO-DE-SOUZA, Marcio GerhardtBipolar disorder (BD) is characterized by unstable mood states ranging from mania to depression. Although there is some evidence that mood instability may result from an imbalance between excitatory glutamatergic and inhibitory GABA-ergic neurotransmission, few proton magnetic resonance spectroscopy (H-1-MRS) studies have measured these two neurometabolites simultaneously in BD. The enzyme glutamic acid decarboxylase (GAD1) catalyzes the decarboxylation of glutamate (Glu) to GABA, and its single nucleotide polymorphisms (SNPs) might influence Glu/GABA ratio. Thus, we investigated Glu/GABA ratio in the dorsal anterior cingulate cortex (dACC) of euthymic BD type I patients and healthy controls (HC), and assessed the influence of both mood stabilizers and GAD1 SNPs on this ratio. Eighty-eight subjects (50 euthymic BD type I patients and 38 HC) underwent 3T H-1-MRS in the dACC (2 x 2 x 4.5 cm(3)) using a two-dimensional JPRESS sequence and all subjects were genotyped for 4 SNPs in the GAD1 gene. BD patients had lower dACC Glu/GABA ratio compared to HC, where this was influenced by anticonvulsant and antipsychotic medications, but not lithium. The presence of GAD1 rs1978340 allele A was associated with higher Glu/GABA ratio in BD, while patients without this allele taking mood stabilizers had a lower Glu/GABA ratio. The lowering of dACC Glu/GABA could be one explanation for the mood stabilizing action of anticonvulsants and antipsychotics in BD type I euthymia. Therefore, this putative role of Glu/GABA ratio and the influence of GAD1 genotype interacting with mood stabilization medication should be confirmed by further studies involving larger samples and other mood states. ClincalTrials.gov registration: NCT01237158.
- Association between CACNA1C gene rs100737 polymorphism and glutamatergic neurometabolites in bipolar disorder(2022) SCOTTI-MUZZI, Estevao; CHILE, Thais; VALLADA, Homero; OTADUY, Maria Concepcion Garcia; SOEIRO-DE-SOUZA, Marcio GerhardtAbnormalities in Ca 2 + homeostasis in Bipolar Disorders (BD) have been associated with impairments in glutamatergic receptors and voltage-gated calcium channels. Increased anterior cingulate cortex (ACC) glutamatergic neurometabolites have been consistently disclosed in BD by proton magnetic resonance spectroscopy ( 1 H-MRS). A single nucleotide polymorphism (SNP) in the CACNA1C gene (rs1006737), which encodes the alpha 1-C subunit of the L-type calcium channel, has been associated with BD and is reported to modulate intra-cellular Ca 2 + . Thus, this study aimed to explore the association of the CACNA1C genotype with ACC glutamatergic metabolites measured by 1 H-MRS in both BD and HC subjects. A total of 194 subjects (121 euthymic BD type I patients and 73 healthy controls (HC) were genotyped for CACNA1C rs1006737, underwent a 3-Tesla 1 H-MRS imaging examination and ACC glutamatergic metabolite were assessed. We found overall increased glutamatergic metabolites in AA carriers in BD. Specifically, higher Glx/Cr was observed in subjects with the AA genotype compared to both AG and GG in the overall sample (BD + HC). Also, female individuals in the BD group with AA genotype were found to have higher Glx/Cr compared to those with other genotypes. CACNA1C AA carriers in use of anticonvulsant medication had higher estimated Glutamine (Glx-Glu) than the other genotypes. Thus, this study suggest an association between calcium channel genetics and in- creased glutamatergic metabolites in BD, possibly playing a synergic role in intracellular Ca2+ overload and excitotoxicity.
- BDNF rs6265 differentially influences neurometabolites in the anterior cingulate of healthy and bipolar disorder subjects(2023) SCOTTI-MUZZI, Estevao; CHILE, Thais; VALLADA, Homero; OTADUY, Maria Concepcion Garcia; SOEIRO-DE-SOUZA, Marcio GerhardtBrain-derived neurotrophic factor (BDNF) is the most abundant brain neurotrophin and plays a critical role in neuronal growth, survival and plasticity, implicated in the pathophysiology of Bipolar Disorders (BD). The single-nucleotide polymorphism in the BDNF gene (BDNF rs6265) has been associated with decreased hippocampal BDNF secretion and volume in met carriers in different populations, although the val allele has been reported to be more frequent in BD patients. The anterior cingulate cortex (ACC) is a key center integrating cognitive and affective neuronal connections, where consistent alterations in brain metabolites such as Glx (Glutamate + Glutamine) and N-acetylaspartate (NAA) have been consistently reported in BD. However, little is known about the influence of BDNF rs6265 on neurochemical profile in the ACC of Healthy Controls (HC) and BD subjects. The aim of this study was to assess the influence of BDNF rs6265 on ACC neurometabolites (Glx, NAA and total creatine- Cr) in 124 euthymic BD type I patients and 76 HC, who were genotyped for BDNF rs6265 and underwent a 3-Tesla proton magnetic resonance imaging and spectroscopy scan ((1) H-MRS) using a PRESS ACC single-voxel (8cm(3)) sequence. BDNF rs6265 polymorphism showed a significant two-way interaction (diagnosis x genotype) in relation to NAA/Cr and total Cr. While met carriers presented increased NAA/Cr in HC, BD-I subjects with the val allele revealed higher total Cr, denoting an enhanced ACC metabolism likely associated with increased glutamatergic metabolites observed in BD-I val carriers. However, these results were replicated only in men. Therefore, our results support evidences that the BDNF rs6265 polymorphism exerts a complex pleiotropic effect on ACC metabolites influenced by the diagnosis and sex.