ANDREA SCHMITT
Projetos de Pesquisa
Unidades Organizacionais
LIM/27 - Laboratório de Neurociências, Hospital das Clínicas, Faculdade de Medicina
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article 89 Citação(ões) na Scopus The role of the cerebellum in schizophrenia: from cognition to molecular pathways(2011) YEGANEH-DOOST, Peyman; GRUBER, Oliver; FALKAI, Peter; SCHMITT, AndreaBeside its role in motor coordination, the cerebellum is involved in cognitive function such as attention, working memory, verbal learning, and sensory discrimination. In schizophrenia, a disturbed prefronto-thalamo-cerebellar circuit has been proposed to play a role in the pathophysiology. In addition, a deficit in the glutamatergic N-methyl-D-aspartate (NMDA) receptor has been hypothesized. The risk gene neuregulin 1 may play a major role in this process. We demonstrated a higher expression of the NMDA receptor subunit 2D in the right cerebellar regions of schizophrenia patients, which may be a secondary upregulation due to a dysfunctional receptor. In contrast, the neuregulin 1 risk variant containing at least one C-allele was associated with decreased expression of NMDA receptor subunit 2C, leading to a dysfunction of the NMDA receptor, which in turn may lead to a dysfunction of the gamma amino butyric acid (GABA) system. Accordingly, from post-mortem studies, there is accumulating evidence that GABAergic signaling is decreased in the cerebellum of schizophrenia patients. As patients in these studies are treated with antipsychotics long term, we evaluated the effect of long-term haloperidol and clozapine treatment in an animal model. We showed that clozapine may be superior to haloperidol in restoring a deficit in NMDA receptor subunit 2C expression in the cerebellum. We discuss the molecular findings in the light of the role of the cerebellum in attention and cognitive deficits in schizophrenia.- Reduction of gyrification index in the cerebellar vermis in schizophrenia: A post-mortem study(2011) SCHMITT, Andrea; SCHULENBERG, Wiebke; BERNSTEIN, Hans-Gert; STEINER, Johann; SCHNEIDER-AXMANN, Thomas; YEGANEH-DOOST, Peyman; MALCHOW, Berend; HASAN, Alkomiet; GRUBER, Oliver; BOGERTS, Bernhard; FALKAI, PeterObjectives. In schizophrenia, alterations of the gyrification index (GI) have been measured in cortical brain regions and are related to neurodevelopmental disturbances. Cerebellar regions have been implicated in the pathophysiolopgy of schizophrenia; however, the GI has not been investigated here so far. Methods. Hence, in a post-mortem study we investigated the GI separately from the vermis, left and right hemisphere of the medial posterior cerebellum in nine schizophrenia patients and 10 healthy controls. GI was defined as length of the inner contour inclusively depth of the sulci divided by length of the outer contour of the cerebellar surface and measured by tracing contours on images obtained by a stereological workstation. Results. In the vermis, GI was reduced in schizophrenia patients according to the methods of Zilles (P = 0.020) and Vogeley (P = 0.015). In the hemispheres, no differences have been observed. GI obtained by the two methods showed a high correlation (P < 0.001). Correlation analysis showed no influence of gender, postmortem interval and age. Conclusions. Decreased GI in the vermis of schizophrenia patients may result from neurodevelopmental disturbances, since folding of the brain occurs mainly during the perinatal period. MRI studies using automated GI processing in larger samples are needed to confirm our results.
- A systematic review of trials investigating strength training in schizophrenia spectrum disorders(2018) KELLER-VARADY, Katriona; VARADY, Patrick A.; ROEH, Astrid; SCHMITT, Andrea; FALKAI, Peter; HASAN, Alkomiet; MALCHOW, BerendThis systematic review analyzed strength training (ST) in patients with schizophrenia. Two independent reviewers searched PubMed and CENTRAL. Only two studies reported on the effects of isolated ST. ST with a single exercise did not improve psychopathology but walking performance. ST for several large muscle groups significantly improved muscle strength and psychopathology. To date, no treatment recommendations can be made for ST. Consistent with recommendations for healthy people combined strength and endurance training can be recommended for schizophrenia. For higher transparency regarding trainings aspects, we recommend for future studies to use the sport science checklist proposed in this paper.
- 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.
- Peptidomic analysis of the anterior temporal lobe and corpus callosum from schizophrenia patients(2017) CAFE-MENDES, C. C.; FERRO, E. S.; TORRAO, A. S.; CRUNFLI, F.; RIOLI, V.; SCHMITT, A.; FALKAI, P.; BRITTO, L. R.; TURCK, C. W.; MARTINS-DE-SOUZA, D.Schizophrenia is a complex disorder hypothesized to develop from a combination of genetic, neurodevelopmental, and environmental factors. Molecules that are directly involved in the pathogenesis of schizophrenia and may serve as biomarker candidates can be identified with ""omics"" approaches such as proteomics and peptidomics. In this context, we performed a peptidomic study in schizophrenia postmortem brains, to our knowledge the first such study in schizophrenia patients. We investigated the anterior temporal lobe (ATL) and corpus callosum (CC) by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and a label-free ion quantification technique based on data-dependent acquisition (DDA). Results indicated alterations in a specific intracellular neurogranin peptide in both the ATL and CC and a decrease of PepH, a fragment of his tone H2B type 1-H intracellular peptide, in the ATL. PepH was tested in serum-deprived Neuro2A cells and showed a protective effect against cell death. Cells were also challenged with lipopolysaccharide (LPS), and PepH was able to prevent the endotoxic effects of LPS. Our data suggest that specific intracellular peptides are altered in schizophrenia patients. The potential biological activity of PepH supports intracellular peptides as novel targets in the study not only of schizophrenia but also of other neuropsychiatric diseases. Biological significance: Psychiatric disorders are considerably more difficult to diagnose in their early stages. Usually, by the time the diagnosis is clear and clinical treatment can be started, the disorder is already established and thus of greater severity. Consequently, the scientific community has been searching for biomarker candidates that can aid the early detection of such disorders and for novel therapeutics to improve treatment or at least delay disease progression. Moreover, key molecules involved in the establishment of psychiatric diseases may help the understanding of their pathogenesis and thus drive the development of more effective treatments. The present work screened peptides that might be possible novel targets to control cell machinery in schizophrenia and identified an intracellular peptide with potential cytoprotective activity. To our knowledge, this is the first peptidomic study in schizophrenia patients.
- Resistance training in patients with schizophrenia: Concept and proof of principle trial(2020) MAURUS, I.; MANTEL, C.; KELLER-VARADY, K.; SCHMITT, A.; LEMBECK, M.; ROEH, A.; PAPAZOVA, I.; FALKAI, P.; SCHNEIDER-AXMANN, T.; HASAN, A.; MALCHOW, B.Resistance training has been shown to contribute to the prevention and management of cardiovascular diseases, which is why it can help reducing morbidity and mortality in schizophrenia patients. Moreover, positive effects on different schizophrenia symptom domains have been proposed. However, a specific resistance training tailored to the needs of schizophrenia patients and its evaluation is still lacking. The objective in this proof of principle trial was to evaluate the feasibility and efficacy of a newly developed 12-week resistance program according to current recommendations of the WHO and the American College of Sports Medicine. We employed a single blind, parallel assignment clinical trial design with participants randomized to attend either a resistance training including three 50min units per week or a balance and tone program as control condition. The primary outcome was the impact on health-related difficulties assessed with the World Health Organization Disability Assessment Schedule (WHO-DAS). Secondary outcome parameters included the level of functioning, schizophrenia symptoms, selected cognitive parameters as well as risk factors for cardiovascular diseases. In our proof of principle trial, we could not find significant time or group effects of resistance training on the WHO-DAS. However, we could observe significant positive effects on the level of functioning assessed with the Global Assessment of Functioning Scale (GAF) over the course of time, which were more pronounced in the intervention group. Our findings indicated that patients with schizophrenia could safely participate in resistance training with relevant improvements in their level of functioning. Well-powered replication trials are needed to provide more efficacy data.
- Differential gene regulation in the anterior cingulate cortex and superior temporal cortex in schizophrenia: A molecular network approach(2021) GEBICKE-HAERTER, Peter J.; LEONARDI-ESSMANN, Fernando; HAERTER, Jan O.; ROSSNER, Moritz J.; FALKAI, Peter; SCHMITT, Andrea; RAABE, Florian J.The closely connected anterior cingulate cortex (ACC) and superior temporal cortex (STC) are important for higher cognitive functions. Both brain regions are disturbed in schizophrenia, i.e., functional and structural alterations have been reported. This postmortem investigation in brains from patients with schizophrenia and controls compared gene expression in the left ACC and left STC. Most differentially expressed genes were unique to each brain region, but some clusters of genes were equally dysregulated in both, giving rise to a more general disease-specific pattern of gene regulation. The data was used to construct a molecular network of the genes identically expressed in both regions as primary nodes and the metabolically connected genes as secondary nodes. The network analysis identified downregulated clusters of immune-associated gene products and upregulated clusters belonging to the ubiquitin-proteasome system. These findings could help to identify new potential therapeutic targets for future approaches.
- Effects of endurance training on brain structures in chronic schizophrenia patients and healthy controls(2016) MALCHOW, Berend; KEESER, Daniel; KELLER, Katriona; HASAN, Alkomiet; RAUCHMANN, Boris-Stephan; KIMURA, Hiroshi; SCHNEIDER-AXMANN, Thomas; DECHENT, Peter; GRUBER, Oliver; ERTL-WAGNER, Birgit; HONER, William G.; HILLMER-VOGEL, Ursula; SCHMITT, Andrea; WOBROCK, Thomas; NIKLAS, Andree; FALKAI, PeterThe objective of this longitudinal magnetic resonance (MR) imaging study was to examine the effects of endurance training on hippocampal and grey matter volumes in schizophrenia patients and healthy controls. 20 chronic schizophrenia patients and 21 age- and gender-matched healthy controls underwent 3months of endurance training (30 min, 3 times per week). 19 additionally recruited schizophrenia patients played table soccer (""foosball"" in the USA) over the same period. MR imaging with 3D-volumetric T1-weighted sequences was performed on a 3 T MR scanner at baseline, after 6 weeks and after the 3-month intervention and 3 additional training-free months. In addition to voxel-based morphometry (VBM), we performed manual and automatic delineation of the hippocampus and its substructures. Endurance capacity and psychopathological symptoms were measured as secondary endpoints. No significant increases in the volumes of the hippocampus or hippocampal substructures were observed in schizophrenia patients or healthy controls. However, VBM analyses displayed an increased volume of the left superior, middle and inferior anterior temporal gyri compared to baseline in schizophrenia patients after the endurance training, whereas patients playing table soccer showed increased volumes in the motor and anterior cingulate cortices. After the additional training-free period, the differences were no longer present. While endurance capacity improved in exercising patients and healthy controls, psychopathological symptoms did not significantly change. The subtle changes in the left temporal cortex indicate an impact of exercise on brain volumes in schizophrenia. Subsequent studies in larger cohorts are warranted to address the question of response variability of endurance training.