MARIA CONCEPCION GARCIA OTADUY
Projetos de Pesquisa
Unidades Organizacionais
Instituto de Radiologia, Hospital das Clínicas, Faculdade de Medicina
LIM/44 - Laboratório de Ressonância Magnética em Neurorradiologia, Hospital das Clínicas, Faculdade de Medicina
LIM/44 - Laboratório de Ressonância Magnética em Neurorradiologia, Hospital das Clínicas, Faculdade de Medicina
16 resultados
Resultados de Busca
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- Increased Brain Lactate During Depressive Episodes and Reversal Effects by Lithium Monotherapy in Drug-Naive Bipolar Disorder A 3-T H-1-MRS Study(2017) MACHADO-VIEIRA, Rodrigo; ZANETTI, Marcus V.; OTADUY, Maria C.; SOUSA, Rafael T. De; SOEIRO-DE-SOUZA, Marcio G.; COSTA, Alana C.; CARVALHO, Andre F.; LEITE, Claudia C.; BUSATTO, Geraldo F.; ZARATE JR., Carlos A.; GATTAZ, Wagner F.Objective: Mitochondrial dysfunction and energy metabolism impairment are key components in the pathophysiology of bipolar disorder (BD) and may involve a shift from aerobic to anaerobic metabolism. Measurement of brain lactate in vivo using protonmagnetic resonance spectroscopy (H-1-MRS) represents an important tool to evaluate mitochondrial and metabolic dysfunction during mood episodes, as well as to monitor treatment response. To date, very few studies have quantified brain lactate in BD. In addition, no study has longitudinally evaluated lactate using H-1-MRS during depressive episodes or its association with mood stabilizer therapy. This study aimed to evaluate cingulate cortex (CC) lactate using 3-T H-1-MRS during acute depressive episodes in BD and the possible effects induced by lithium monotherapy. Methods: Twenty medication-free outpatients with short length of BD (80% drug-naive) in a current major depressive episode were matched with control subjects. Patients were treated for 6 weeks with lithium monotherapy at therapeutic doses in an open-label trial (blood level, 0.48 +/- 0.19 mmol/L). Cingulate cortex lactate was measured before (week 0) and after lithium therapy (week 6) using H-1-MRS. Antidepressant efficacy was assessed with the 21-item Hamilton Depression Rating Scale as the primary outcome. Results: Subjects with BD depression showed a significantly higher CC lactate in comparison to control subjects. Furthermore, a significant decrease in CC lactate was observed after 6 weeks of lithium treatment compared with baseline (P = 0.002). CC Lactate levels was associated with family history of mood disorders and plasma lithium levels. Conclusions: This is the first report of increased CC lactate in patients with bipolar depression and lower levels after lithium monotherapy for 6 weeks. These findings indicate a shift to anaerobic metabolism and a role for lactate as a state marker during mood episodes. Energy and redox dysfunction may represent key targets for lithium's therapeutic actions.
- Dorsal Anterior Cingulate Lactate and Glutathione Levels in Euthymic Bipolar I Disorder: H-1-MRS Study(2016) SOEIRO-DE-SOUZA, Marcio Gerhardt; PASTORELLO, Bruno F.; LEITE, Claudia da Costa; HENNING, Anke; MORENO, Ricardo A.; OTADUY, Maria Concepcion GarciaOxidative stress and mitochondrial dysfunction are 2 closely integrated processes implicated in the physiopathology of bipolar disorder. Advanced proton magnetic resonance spectroscopy techniques enable the measurement of levels of lactate, the main marker of mitochondrial dysfunction, and glutathione, the predominant brain antioxidant. The objective of this study was to measure brain lactate and glutathione levels in bipolar disorder and healthy controls. Eighty-eight individuals (50 bipolar disorder and 38 healthy controls) underwent 3T proton magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (2x2x4.5cm(3)) using a 2-D JPRESS sequence. Lactate and glutathione were quantified using the ProFit software program. Bipolar disorder patients had higher dorsal anterior cingulate cortex lactate levels compared with controls. Glutathione levels did not differ between euthymic bipolar disorder and controls. There was a positive correlation between lactate and glutathione levels specific to bipolar disorder. No influence of medications on metabolites was observed. This is the most extensive magnetic resonance spectroscopy study of lactate and glutathione in bipolar disorder to date, and results indicated that euthymic bipolar disorder patients had higher levels of lactate, which might be an indication of altered mitochondrial function. Moreover, lactate levels correlated with glutathione levels, indicating a compensatory mechanism regardless of bipolar disorder diagnosis.
- Effect of age, diet, and tissue type on PCr response to creatine supplementation(2017) SOLIS, Marina Yazigi; ARTIOLI, Guilherme Giannini; OTADUY, Maria Concepcion Garcia; LEITE, Claudia da Costa; ARRUDA, Walquiria; VEIGA, Raquel Ramos; GUALANO, BrunoCreatine/phosphorylcreatine (PCr) responses to creatine supplementation may be modulated by age, diet, and tissue, but studies assessing this possibility are lacking. Therefore we aimed to determine whether PCr responses vary as a function of age, diet, and tissue. Fifteen children, 17 omnivorous and 14 vegetarian adults, and 18 elderly individuals (""elderly"") participated in this study. Participants were given placebo and subsequently creatine (0.3 g center dot kg(-1) center dot day(-1)) for 7 days in a singleblind fashion. PCr was measured through phosphorus magnetic resonance spectroscopy (P-31-MRS) in muscle and brain. Creatine supplementation increased muscle PCr in children (P < 0.0003) and elderly (P < 0.001), whereas the increase in omnivores did not reach statistically significant difference (P < 0.3348). Elderly had greater PCr increases than children and omnivores (P < 0.0001 for both), whereas children experienced greater PCr increases than omnivores (P < 0.0022). In relation to diet, vegetarians (P < 0.0001), but not omnivores, had significant increases in muscle PCr content. Brain PCr content was not affected by creatine supplementation in any group, and delta changes in brain PCr (-0.7 to +3.9%) were inferior to those in muscle PCr content (+10.3 to +27.6%; P < 0.0001 for all comparisons). PCr responses to a standardized creatine protocol (0.3 g center dot kg(-1) center dot day(-1) for 7 days) may be affected by age, diet, and tissue. Whereas creatine supplementation was able to increase muscle PCr in all groups, although to different extents, brain PCr was shown to be unresponsive overall. These findings demonstrate the need to tailor creatine protocols to optimize creatine/PCr accumulation both in muscle and in brain, enabling a better appreciation of the pleiotropic properties of creatine. NEW & NOTEWORTHY A standardized creatine supplementation protocol (0.3 g center dot kg(-1) center dot day(-1) for 7 days) effectively increased muscle, but not brain, phosphorylcreatine. Older participants responded better than younger participants whereas vegetarians responded better than omnivores. Responses to supplementation are thus dependent on age, tissue, and diet. This suggests that a single ""universal"" protocol, originally designed for increasing muscle creatine in young individuals, may lead to heterogeneous muscle responses in different populations or even no responses in tissues other than skeletal muscle.
- Lithium-associated anterior cingulate neurometabolic profile in euthymic Bipolar I disorder: A H-1-MRS study(2018) SOEIRO-DE-SOUZA, Marcio Gerhardt; OTADUY, Maria Concepcion Garcia; MACHADO-VIEIRA, Rodrigo; MORENO, Ricardo Alberto; NERY, Fabiano G.; LEITE, Claudia; LAFER, BenyObjective: In the treatment of Bipolar disorder (BD), achieving euthymia is highly complex and usually requires a combination of mood stabilizers. The mechanism of action in stabilizing mood has not been fully elucidated, but alterations in N-Acetylaspartate (NAA), Myo-Inositol (mI) and Choline (Cho) have been implicated. Proton magnetic resonance spectroscopy (H-1-MRS) is the gold standard technique for measuring brain NAA, Cho and mI in vivo. The objective of this study was to investigate the association of lithium use in BD type I and brain levels of NAA, mI and Cho in the (anterior cingulate cortex) ACC. Methods: 129 BD type I subjects and 79 healthy controls (HC) were submitted to a 3-Tesla brain magnetic resonance imaging scan (H-1-MRS) using a PRESS ACC single voxel (8cm(3)) sequence. Results: BD patients exhibited higher NAA and Cho levels compared to HC. Lithium prescription was associated with lower mI (combination + monotherapy) and higher NAA levels (monotherapy). Conclusion: The results observed add to the knowledge about the mechanisms of action of mood stabilizers on brain metabolites during euthymia. Additionally, the observed decrease in mI levels associated with lithium monotherapy is an in vivo finding that supports the inositol-depletion hypothesis of lithium pharmacodynamics.
- Bimodal Effect of Lithium Plasma Levels on Hippocampal Glutamate Concentrations in Bipolar II Depression: A Pilot Study(2015) ZANETTI, Marcus V.; OTADUY, Maria C.; SOUSA, Rafael T. de; GATTAZ, Wagner F.; BUSATTO, Geraldo F.; LEITE, Claudia C.; MACHADO-VIEIRA, RodrigoBackground: The hippocampus has been highly implicated in the pathophysiology of bipolar disorder (BD). Nevertheless, no study has longitudinally evaluated hippocampal metabolite levels in bipolar depression under treatment with lithium. Methods: Nineteen medication-free BD patients (78.9% treatment-naive and 73.7% with BD type II) presenting an acute depressive episode and 17 healthy controls were studied. Patients were treated for 6 weeks with lithium in an open-label trial. N-acetyl aspartate (NAA), creatine, choline, myo-Inositol, and glutamate levels were assessed in the left hippocampus before (week 0) and after (week 6) lithium treatment using 3T proton magnetic resonance spectroscopy (1H-MRS). The metabolite concentrations were estimated using internal water as reference and voxel segmentation for partial volume correction. Results: At baseline, acutely depressed BD patients and healthy controls exhibited similar hippocampal metabolites concentrations, with no changes after 6 weeks of lithium monotherapy. A significant correlation between antidepressant efficacy and increases in NAA concentration over time was observed. Also, there was a significant positive correlation between the changes in glutamate concentrations over follow-up and plasma lithium levels at endpoint. Mixed effects model analysis revealed a bimodal effect of lithium plasma levels in hippocampal glutamate concentrations: levels of 0.2 to 0.49 mmol/L (n=9) were associated with a decrease in glutamate concentrations, whereas the subgroup of BD subjects with ""standard"" lithium levels (>= 0.50 mmol/L; n = 10) showed an overall increase in glutamate concentrations over time. Conclusions: These preliminary results suggest that lithium has a bimodal action in hippocampal glutamate concentration depending on the plasma levels.
- 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.
- A Longitudinal (6-week) 3T H-1-MRS Study on the Effects of Lithium Treatment on Anterior Cingulate Cortex Metabolites in Bipolar Depression(2015) MACHADO-VIEIRA, Rodrigo; GATTAZ, Wagner F.; ZANETTI, Marcus V.; SOUSA, Rafael T. De; CARVALHO, Andre F.; SOEIRO-DE-SOUZA, Marcio G.; LEITE, Claudia C.; OTADUY, Maria C.The anterior cingulate cortex (ACC) is a key area in mood regulation. To date, no Longitudinal study has specifically evaluated lithium's effects on ACC metabolites using H-1-MRS, as well as its association with clinical improvement in bipolar depression. This H-1-MRS (TE=35 ms) study evaluated 24 drug-free BD patients during depressive episodes and after lithium treatment at therapeutic levels. Brain metabolite levels (N-acetyl aspartate (NM), creatine (tCr), choline, myo-inositol, and glutamate levels) were measured in the ACC at baseline (week 0) and after lithium monotherapy (week 6). The present investigation showed that ACC glutamate (Glu/tCr) and glutamate +glutamine (Glx/tCr) significantly increased after six weeks of lithium therapy. Regarding the association with clinical improvement, remitters showed an increase in myoinositol levels (ml/tCr) after lithium treatment compared to non-remitters. The present findings reinforce a role for ACC glutamate-glutamine cycling and myoinositol pathway as key targets for lithium's therapeutic effects in BD.
- Frequency drift in MR spectroscopy at 3T(2021) HUI, Steve C. N.; MIKKELSEN, Mark; ZOLLNER, Helge J.; AHLUWALIA, Vishwadeep; ALCAUTER, Sarael; BALTUSIS, Laima; BARANY, Deborah A.; BARLOW, Laura R.; BECKER, Robert; I, Jeffrey Berman; BERRINGTON, Adam; BHATTACHARYYA, Pallab K.; BLICHER, Jakob Udby; BOGNER, Wolfgang; BROWN, Mark S.; CALHOUN, Vince D.; CASTILLO, Ryan; CECIL, Kim M.; CHOI, Yeo Bi; CHU, Winnie C. W.; CLARKE, William T.; CRAVEN, Alexander R.; CUYPERS, Koen; DACKO, Michael; FUENTE-SANDOVAL, Camilo de la; DESMOND, Patricia; DOMAGALIK, Aleksandra; DUMONT, Julien; DUNCAN, Niall W.; DYDAK, Ulrike; DYKE, Katherine; EDMONDSON, David A.; ENDE, Gabriele; ERSLAND, Lars; EVANS, C. John; FERMIN, Alan S. R.; FERRETTI, Antonio; FILLMER, Ariane; GONG, Tao; GREENHOUSE, Ian; GRIST, James T.; GU, Meng; HARRIS, Ashley D.; HATZ, Katarzyna; HEBA, Stefanie; HECKOVA, Eva; HEGARTY, John P.; HEISE, Kirstin-Friederike; HONDA, Shiori; JACOBSON, Aaron; JANSEN, Jacobus F. A.; JENKINS, Christopher W.; JOHNSTON, Stephen J.; JUCHEM, Christoph; KANGARLU, Alayar; KERR, Adam B.; LANDHEER, Karl; LANGE, Thomas; LEE, Phil; LEVENDOVSZKY, Swati Rane; LIMPEROPOULOS, Catherine; LIU, Feng; LLOYD, William; LYTHGOE, David J.; MACHIZAWA, Maro G.; MACMILLAN, Erin L.; MADDOCK, Richard J.; V, Andrei Manzhurtsev; MARTINEZ-GUDINO, Maria L.; MILLER, Jack J.; MIRZAKHANIAN, Heline; MORENO-ORTEGA, Marta; MULLINS, Paul G.; NAKAJIMA, Shinichiro; NEAR, Jamie; NOESKE, Ralph; NORDHOY, Wibeke; OELTZSCHNER, Georg; OSORIO-DURAN, Raul; OTADUY, Maria C. G.; PASAYE, Erick H.; PEETERS, Ronald; PELTIER, Scott J.; PILATUS, Ulrich; POLOMAC, Nenad; PORGES, Eric C.; PRADHAN, Subechhya; PRISCIANDARO, James Joseph; PUTS, Nicolaas A.; RAE, Caroline D.; REYES-MADRIGAL, Francisco; ROBERTS, Timothy P. L.; ROBERTSON, Caroline E.; ROSENBERG, Jens T.; ROTARU, Diana-Georgiana; TUURA, Ruth L. O'Gorman; SALEH, Muhammad G.; SANDBERG, Kristian; SANGILL, Ryan; SCHEMBRI, Keith; SCHRANTEE, Anouk; SEMENOVA, Natalia A.; SINGEL, Debra; SITNIKOV, Rouslan; SMITH, Jolinda; SONG, Yulu; STARK, Craig; STOFFERS, Diederick; SWINNEN, Stephan P.; TAIN, Rongwen; TANASE, Costin; TAPPER, Sofie; TEGENTHOFF, Martin; THIEL, Thomas; THIOUX, Marc; TRUONG, Peter; DIJK, Pim van; VELLA, Nolan; VIDYASAGAR, Rishma; VOVK, Andrej; WANG, Guangbin; WESTLYE, Lars T.; WILBUR, Timothy K.; WILLOUGHBY, William R.; WILSON, Martin; WITTSACK, Hans-Jorg; WOODS, Adam J.; WU, Yen-Chien; XU, Junqian; LOPEZ, Maria Yanez; YEUNG, David K. W.; ZHAO, Qun; ZHOU, Xiaopeng; ZUPAN, Gasper; EDDEN, Richard A. E.Purpose: Heating of gradient coils and passive shim components is a common cause of instability in the B-0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. Method: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). Results: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. Discussion: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.
- 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.