ANDREA SCHMITT
Projetos de Pesquisa
Unidades Organizacionais
LIM/27 - Laboratório de Neurociências, Hospital das Clínicas, Faculdade de Medicina
29 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 29
- New treatment strategies for mental health(2023) HASHIMOTO, Kenji; SCHMITT, Andrea
- Association between altered hippocampal oligodendrocyte number and neuronal circuit structures in schizophrenia: a postmortem analysis(2020) FALKAI, Peter; RAABE, Florian; BOGERTS, Bernhard; SCHNEIDER-AXMANN, Thomas; MALCHOW, Berend; TATSCH, Laura; HUBER, Verena; SLAPAKOVA, Lenka; DOBROWOLNY, Henrik; SCHMITZ, Christoph; CANTUTI-CASTELVETRI, Ludovico; SIMONS, Mikael; STEINER, Johann; SCHMITT, AndreaIn schizophrenia, decreased hippocampal volume, reduced oligodendrocyte numbers in hippocampal cornu ammonis (CA) subregions and reduced neuron number in the dentate gyrus have been reported; reduced oligodendrocyte numbers were significantly related to cognitive deficits. The hippocampus is involved in cognitive functions and connected to the hypothalamus, anterior thalamus, and cingulate cortex, forming the Papez circuit, and to the mediodorsal thalamus. The relationship between the volume of these interconnected regions and oligodendrocyte and neuron numbers in schizophrenia is unknown. Therefore, we used stepwise logistic regression with subsequent multivariate stepwise linear regression and bivariate correlation to analyze oligodendrocyte and neuron numbers in the posterior hippocampal subregions CA1, CA2/3, CA4, dentate gyrus, and subiculum and volumes of the hippocampal CA region, cingulum, anterior and mediodorsal thalamus and hypothalamus in postmortem brains of 10 schizophrenia patients and 11 age- and gender-matched healthy controls. Stepwise logistic regression identified the following predictors for diagnosis, in order of inclusion: (1) oligodendrocyte number in CA4, (2) hypothalamus volume, (3) oligodendrocyte number in CA2/3, and (4) mediodorsal thalamus volume. Subsequent stepwise linear regression analyses identified the following predictors: (1) for oligodendrocyte number in CA4: (a) oligodendrocyte number in CA2/3, (b) diagnostic group, (c) hypothalamus volume, and (d) neurons in posterior subiculum; (2) for hypothalamus volume: (a) mediodorsal thalamus volume; (3) for oligodendrocyte number in CA2/3: oligodendrocyte number (a) in posterior CA4 and (b) in posterior subiculum; (4) for mediodorsal thalamus volume: volumes of (a) anterior thalamus and (b) hippocampal CA. In conclusion, we found a positive relationship between hippocampal oligodendrocyte number and the volume of the hypothalamus, a brain region connected to the hippocampus, which is important for cognition.
- Improvement in daily functioning after aerobic exercise training in schizophrenia is sustained after exercise cessation(2021) FALKAI, Peter; MAURUS, Isabel; SCHMITT, Andrea; MALCHOW, Berend; SCHNEIDER-AXMANN, Thomas; ROELL, Lukas; PAPIOL, Sergi; WOBROCK, Thomas; HASAN, Alkomiet; KEESER, Daniel
- Structural synaptic elements are differentially regulated in superior temporal cortex of schizophrenia patients(2012) SCHMITT, Andrea; LEONARDI-ESSMANN, Fernando; DURRENBERGER, Pascal F.; WICHERT, Sven P.; SPANAGEL, Rainer; ARZBERGER, Thomas; KRETZSCHMAR, Hans; ZINK, Mathias; HERRERA-MARSCHITZ, Mario; REYNOLDS, Richard; ROSSNER, Moritz J.; FALKAI, Peter; GEBICKE-HAERTER, Peter J.Inaccurate wiring and synaptic pathology appear to be major hallmarks of schizophrenia. A variety of gene products involved in synaptic neurotransmission and receptor signaling are differentially expressed in brains of schizophrenia patients. However, synaptic pathology may also develop by improper expression of intra- and extra-cellular structural elements weakening synaptic stability. Therefore, we have investigated transcription of these elements in the left superior temporal gyrus of 10 schizophrenia patients and 10 healthy controls by genome-wide microarrays (Illumina). Fourteen up-regulated and 22 downregulated genes encoding structural elements were chosen from the lists of differentially regulated genes for further qRT-PCR analysis. Almost all genes confirmed by this method were downregulated. Their gene products belonged to vesicle-associated proteins, that is, synaptotagmin 6 and syntaxin 12, to cytoskeletal proteins, like myosin 6, pleckstrin, or to proteins of the extracellular matrix, such as collagens, or laminin C3. Our results underline the pivotal roles of structural genes that control formation and stabilization of pre- and post-synaptic elements or influence axon guidance in schizophrenia. The glial origin of collagen or laminin highlights the close interrelationship between neurons and glial cells in establishment and maintenance of synaptic strength and plasticity. It is hypothesized that abnormal expression of these and related genes has a major impact on the pathophysiology of schizophrenia.
- S100B is downregulated in the nuclear proteome of schizophrenia corpus callosum(2014) STEINER, Johann; SCHMITT, Andrea; SCHROETER, Matthias L.; BOGERTS, Bernhard; FALKAI, Peter; TURCK, Christoph W.; MARTINS-DE-SOUZA, DanielHere we report the downregulation of S100B in the nuclear proteome of the corpus callosum from nine schizophrenia patients compared to seven mentally healthy controls. Our data have been obtained primarily by mass spectrometry and later confirmed by Western blot. This is an intriguing finding coming from a brain region which is essentially composed by white matter, considering the potential role of S100B in the control of oligodendrocyte maturation. This data reinforce the importance of oligodendrocytes in schizophrenia, shedding more light to its pathobiology.
- Differential expression of HINT1 in schizophrenia brain tissue(2012) VARADARAJULU, Jeeva; SCHMITT, Andrea; FALKAI, Peter; ALSAIF, Murtada; TURCK, Christoph W.; MARTINS-DE-SOUZA, DanielRecent findings in the literature suggest a relation between histidine triad nucleotide-binding protein-1 (HINT1) and psychiatric disorders such as major depression, anxiety, and schizophrenia, although its physiological roles are not completely comprehended. Using Western blot, we compared HINT1 protein expression in the postmortem dorsolateral prefrontal cortex and thalamus of schizophrenia patients and healthy controls for contributing to elucidate the role of HINT1 in schizophrenia pathophysiology. HINT1 was found to be downregulated in the dorsolateral prefrontal cortex and upregulated in the thalamus. Our results combined to previous studies in human samples and preclinical models support the notion that HINT1 must be more explored as a potential target for psychiatric disorders.
- Association between aerobic fitness and the functional connectome in patients with schizophrenia(2022) ROELL, Lukas; MAURUS, Isabel; KEESER, Daniel; KARALI, Temmuz; PAPAZOV, Boris; HASAN, Alkomiet; SCHMITT, Andrea; PAPAZOVA, Irina; LEMBECK, Moritz; HIRJAK, Dusan; SYKOROVA, Eliska; THIEME, Cristina E.; MUENZ, Susanne; SEITZ, Valentina; GRESKA, David; CAMPANA, Mattia; WAGNER, Elias; LOEHRS, Lisa; STOECKLEIN, Sophia; ERTL-WAGNER, Birgit; POEMSL, Johannes; ROEH, Astrid; MALCHOW, Berend; KELLER-VARADY, Katriona; MEYER-LINDENBERG, Andreas; FALKAI, PeterBackground Schizophrenia is accompanied by widespread alterations in static functional connectivity associated with symptom severity and cognitive deficits. Improvements in aerobic fitness have been demonstrated to ameliorate symptomatology and cognition in people with schizophrenia, but the intermediary role of macroscale connectivity patterns remains unknown. Objective Therefore, we aim to explore the relation between aerobic fitness and the functional connectome in individuals with schizophrenia. Further, we investigate clinical and cognitive relevance of the identified fitness-connectivity links. Methods Patients diagnosed with schizophrenia were included in this cross-sectional resting-state fMRI analysis. Multilevel Bayesian partial correlations between aerobic fitness and functional connections across the whole brain as well as between static functional connectivity patterns and clinical and cognitive outcome were performed. Preliminary causal inferences were enabled based on mediation analyses. Results Static functional connectivity between the subcortical nuclei and the cerebellum as well as between temporal seeds mediated the attenuating relation between aerobic fitness and total symptom severity. Functional connections between cerebellar seeds affected the positive link between aerobic fitness and global cognition, while the functional interplay between central and limbic seeds drove the beneficial association between aerobic fitness and emotion recognition. Conclusion The current study provides first insights into the interactions between aerobic fitness, the functional connectome and clinical and cognitive outcome in people with schizophrenia, but causal interpretations are preliminary. Further interventional aerobic exercise studies are needed to replicate the current findings and to enable conclusive causal inferences.
- Effects of haloperidol and clozapine on synapse-related gene expression in specific brain regions of male rats(2018) WILMSDORFF, Martina von; MANTHEY, Fabian; BOUVIER, Marie-Luise; STAEHLIN, Oliver; FALKAI, Peter; MEISENZAHL-LECHNER, Eva; SCHMITT, Andrea; GEBICKE-HAERTER, Peter J.We investigated the effects of clozapine and haloperidol, drugs that are widely used in the treatment of schizophrenia, on gene expression in six cortical and subcortical brain regions of adult rats. Drug treatments started at postnatal day 85 and continued over a 12-week period. Ten animals received haloperidol (1 mg/kg bodyweight) and ten received clozapine (20 mg/kg bodyweight) orally each day. Ten control rats received no drugs. The ten genes selected for this study did not belong to the dopaminergic or serotoninergic systems, which are typically targeted by the two substances, but coded for proteins of the cytoskeleton and proteins belonging to the synaptic transmitter release machinery. Quantitative real-time PCR was performed in the prelimbic cortex, cingulate gyrus (CG1) and caudate putamen and in the hippocampal cornu ammonis 1 (CA1), cornu ammonis 3 (CA3) and dentate gyrus. Results show distinct patterns of gene expression under the influence of the two drugs, but also distinct gene regulations dependent on the brain regions. Haloperidol-medicated animals showed statistically significant downregulation of SNAP-25 in CA3 (p = 0.0134) and upregulation of STX1A in CA1 (p = 0.0133) compared to controls. Clozapine-treated animals showed significant downregulation of SNAP-25 in CG1 (p = 0.0013). Our results clearly reveal that the drugs' effects are different between brain regions. These effects are possibly indirectly mediated through feedback mechanisms by proteins targeted by the drugs, but direct effects of haloperidol or clozapine on mechanisms of gene expression cannot be excluded.
- Reduced cortical neuron number and neuron density in schizophrenia with focus on area 24: a post-mortem case-control study(2023) GAUS, Richard; POPAL, Melanie; HEINSEN, Helmut; SCHMITT, Andrea; FALKAI, Peter; HOF, Patrick R.; SCHMITZ, Christoph; VOLLHARDT, AlisaStructural and functional abnormalities of the anterior cingulate cortex (ACC) have frequently been identified in schizophrenia. Alterations of von Economo neurons (VENs), a class of specialized projection neurons, have been found in different neuropsychiatric disorders and are also suspected in schizophrenia. To date, however, no definitive conclusions can be drawn about quantitative histologic changes in the ACC in schizophrenia because of a lack of rigorous, design-based stereologic studies. In the present study, the volume, total neuron number and total number of VENs in layer V of area 24 were determined in both hemispheres of postmortem brains from 12 male patients with schizophrenia and 11 age-matched male controls. To distinguish global from local effects, volume and total neuron number were also determined in the whole area 24 and whole cortical gray matter (CGM). Measurements were adjusted for hemisphere, age, postmortem interval and fixation time using an ANCOVA model. Compared to controls, patients with schizophrenia showed alterations, with lower mean total neuron number in CGM (- 14.9%, P = 0.007) and in layer V of area 24 (- 21.1%, P = 0.002), and lower mean total number of VENs (- 28.3%, P = 0.027). These data provide evidence for ACC involvement in the pathophysiology of schizophrenia, and complement neuroimaging findings of impaired ACC connectivity in schizophrenia. Furthermore, these results support the hypothesis that the clinical presentation of schizophrenia, particularly deficits in social cognition, is associated with pathology of VENs.
- Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders(2013) HASHIMOTO, Kenji; MALCHOW, Berend; FALKAI, Peter; SCHMITT, AndreaSevere psychiatric disorders such as schizophrenia are related to cognitive and negative symptoms, which often are resistant to current treatment approaches. The glutamatergic system has been implicated in the pathophysiology of schizophrenia and affective disorders. A key component is the dysfunction of the glutamatergic N-methyl-d-aspartate (NMDA) receptor. Substances regulating activation/inhibition of the NMDA receptor have been investigated in schizophrenia and major depression and are promising in therapeutic approaches of negative symptoms, cognition, and mood. In schizophrenia, add-on treatments with glycine, d-serine, d-alanine, d-cycloserine, d-amino acid oxidase inhibitors, glycine transporter-1 (GlyT-1) inhibitors (e.g., sarcosine, bitopertin) and agonists (e.g., LY2140023) or positive allosteric modulator (e.g., ADX71149) of group II metabotropic glutamate receptors (mGluRs) have been studied. In major depression, the NMDA receptor antagonists (e.g., ketamine, AZD6765), GluN2B subtype antagonists (e.g., traxoprodil, MK-0657), and partial agonists (e.g., d-cycloserine, GLYX-13) at the glycine site of the NMDA receptor have been proven to be effective in animal studies and first clinical trials. In addition, clinical studies of mGluR2/3 antagonist BCI-838 (a prodrug of BCI-632 (MGS0039)), mGluR2/3-negative allosteric modulators (NMAs) (e.g., RO499819, RO4432717), and mGluR5 NAMs (e.g., AZD2066, RO4917523) are in progress. Future investigations should include effects on brain structure and activation to elucidate neural mechanisms underlying efficacy of these drugs.
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