Es mehren sich die Hinweise, dass Umwelteinflüsse wie Stress und Mangelernährung während der frühen Entwicklung im Mutterleib einen wesentlichen Einfluss auf die Gesundheit im späteren Leben haben. Die durch diese Umwelteinflüsse induzierten epigenetischen Veränderungen tragen zur Prädisposition für „Volkskrankheiten“ wie Depressionen, Adipositas und kardiovaskulären Erkrankungen bei. Die epigenetischen Veränderungen erklären auch die Persistenz dieser Erkrankungen über Generationen und die schlechte Wirksamkeit präventiver oder interventioneller Maßnahmen im Erwachsenenalter.
Normale Hirnentwicklung und Reifung der Hirnfunktion
Wie schon die Erfahrung jeder Mutter zeigt, wechseln in utero Phasen der Ruhe mit Phasen der körperlichen Aktivität. Diese Verhaltensänderungen reflektieren die fetalen Schlafstadien. Wir untersuchen die Entwicklung der fetalen Schlafstadien als globaler Marker für den Entwicklungsstand der Hirnfunktion.
Hören und Fühlen im Mutterleib
Heftige mütterliche Bewegungen oder äußere Geräusche werden durch den Fetus mit ausgeprägten Körperbewegungen aber auch mit Änderungen der Herzfrequenz, Augen- und Atembewegungen beantwortet. Unser Verständnis, wann und wie sich Hören und Fühlen im Mutterleib entwickelt und welche Bedeutung Umweltreize für die fetale Hirnentwicklung haben, ist noch marginal.
Ziel unserer Untersuchungen ist besser zu verstehen,
inwiefern vibroakustische (Schwingungen und Geräusche) und somatosensible (z.B. Uteruskontrakturen) Reize als die wesentlichen Stimuli aus der äußeren Umwelt durch den Feten wahrgenommen werden
wie sich die zerebrale Reizverarbeitung von vibroakustischen und somatosensiblen Stimuli während der Fetalperiode entwickelt
welche Perzeptionswege für die Wahrnehmung vibroakustischer Stimuli in Frage kommen (z.B. Knochenleitung, Schallübertragung durch die Bauchwand)
welche Rolle vibroakustische und somatosensible Reize für die Hirnentwicklung spielen
Fetale Programmierung von kardio- und zerebrovaskulären Erkrankungen sowie Verhaltensauffälligkeiten im späteren Leben
Wesentliche Umwelteinflüsse, die die Gesundheit im späteren Leben determinieren, sind mütterlicher Stress, Mangelernährung und Obesitas während der Schwangerschaft, denn sie können zu dauerhaften Modifikationen von physiologischen Systemen wie der Stressachse oder des Verdauungssystems führen. Auf mechanistischer Ebene induzieren diese Umwelteinflüsse Veränderungen der Reifung fetaler Organsysteme wie des Gehirns, des kardiovaskulären, metabolischen oder Immunsystems. Zum Beispiel führen funktionelle Anpassungen des Feten an Stress zu einer erhöhten Stresssensitivität und ermöglichen eine Adaptation an eine feindliche Umgebung nach der Geburt. Eine intrauterine Mangelernährung bewirkt eine Programmierung auf guter „Futterverwerter“ und sichert das Überleben bei Nahrungsmangel. Diese Anpassungen haben jedoch auch pathogenetisches Potential insbesondere wenn die „erwarteten“ Umweltbedingungen nicht eintreffen. Eine erhöhte Stressempfindlichkeit kann zu stressassoziierten Erkrankungen wie neuropsychiatrischen Auffälligkeiten (kognitive Störungen, ADHS, Depressionen) oder kardiovaskulären Erkrankungen (Herzinfarkte, Schlaganfälle) führen. Eine zu gute „Futterverwertung“ kann bei normaler Nahrungszufuhr metabolische Störungen (Diabetes, Obesitas) induzieren. Aber auch adipöse Mütter können eine Prädisposition für Obesitas „vererben“. Dies geschieht möglicherweise über Veränderungen im kindlichen Mikrobiom. Veränderungen der Hirnentwicklung, die alle drei Umwelteinflüsse potentiell induzieren, können zu Einbußen in der kognitiven Leistungsfähigkeit führen.
Wir beschäftigen uns insbesondere mit
Übertragungswegen von mütterlichem Stress auf den Fetus
epigenetischen Mechanismen der fetalen Programmierung
Auswirkungen von pränataler Fehlernährung (mütterliche Mangelernährung und Obesitas) und pränatalem Stress auf die fetale Reifung des Gehirns, der Stressachse, des Immunsystems und des kardiovaskulären Systems
den Effekten von pränataler Fehlernährung und pränatalem Stress auf die Funktion dieser Organsysteme im späteren Leben
Die Ergebnisse experimenteller Untersuchungen an Nagermodellen und im chronisch instrumentierten fetalen Schaf werden in klinischen Kohortenstudien verifiziert (von bench to bedside). Umgekehrt werden die Mechanismen von in klinischen Kohortenstudien gefundenen Effekten experimentell untersucht, um frühe präventive Maßnahmen zu entwickeln.
Die intrauterine hypoxische Hinschädigung (zerebrale Leukomalazie) und damit assoziierte Hirnblutungen werden durch eine Exposition gegenüber Glukokortikoiden beeinflusst. Wir beschäftigen uns mit den darunter liegenden Pathomechanismen.
Impact of Prenatal Stress on brain ageing Fetal programming, undernutrition and stress
Our Mission Slowing brain ageing and susceptibility to age-associated diseases: Early programming of pathways and genes and late interventional targets.
Committed to healthy brain ageing from the very beginning A healthy brain is a major determinant of good life-long health. Human epidemiological and animal studies indicate that in addition to life style and genetic factors, environmental influences in prenatal life have a major impact on brain ageing and age-associated brain disorders.
Our consortium consists of leading European and US-American neuroscientists, physiologists, obstetricians, developmental psychologists and innovative biotech companies.
Our project will determine structural and functional indicators of brain age. We examine to what extent prenatal stress, i.e. maternal stress, glucocorticoid treatment or malnutrition, mediate premature brain ageing and susceptibility to age-associated brain disorders such as cognitive decline and stroke.
We dissect mechanisms and pharmacological interventions which may be used in elderly people. Information obtained will allow identification of people at risk for premature brain ageing and offer therapeutic interventions.
Human epidemiological and animal studies indicate that in addition to life style and genetic factors, environmental influences in prenatal life have a major impact on brain ageing and age-associated brain disorders. We hypothesize that: (1) prenatal stress i.e. maternal stress, treatment with stress hormones (glucocorticoids) and undernutrition programs early brain ageing; (2) this predisposes to age-associated brain diseases including cognitive decline and stroke; (3) epigenetic changes affecting glucocorticoid receptor sensitivity, altered autonomic nervous system reactivity and altered cerebrovascular tone are important mediators of these processes, (4) these changes represent targets for diagnosis, preventive measures and therapeutic interventions. Stress is increasingly prevalent in today’s society and a stress sensitive brain is particularly vulnerable for an early loss of brain resilience to challenges.
Our consortium has unique access to well-defined human and non-human primate cohorts at different ages from early childhood to the elderly that have been exposed to different types of prenatal stress. For experimental analysis of mechanisms of prenatal programming, we apply innovative techniques to characterize brain ageing, namely MRI based volumetry, non-linear analysis of EEG and autonomous activity, advanced molecular techniques including epigenetics, metabolomics and neuropsychological as well as behavioral tests.
Effects and mechanisms of prenatal programming The relationship between prenatal programming and ageing is undoubtedly complex involving several factors, pathways and mechanisms which appear to be critical for early brain ageing. We concentrate on linking early developmental processes with longevity and ageing with a special focus on genes and pathways. In an integrated and translational approach, this project addresses the key question “How sensitive is the stress axis to major environmental stimuli during pregnancy and how persistent are the changes throughout the entire life-span including ageing?” The project analyzes to what extent glucocorticoid receptor resistance, increased sympathetic activity, or increased cerebrovascular tone are key mediators connecting developmental modifications to early brain ageing and increased susceptibility to age-associated brain disorders in experimental studies. We will show to what extent prenatal stress programs early cognitive decline together with incidence and outcome of stroke in aged subjects. We compare the impact of different types of prenatal stress: maternal psychophysiological stress, undernutrition, and therapeutic exposure to stress hormones (glucocorticoids). The results achieved in the project will reveal to what extent the different types of prenatal stress program early brain ageing. We have access to some of the best characterized human cohorts at different ages from early childhood to the elderly that have been exposed to prenatal stress to examine and compare the effects of major prenatal environmental factors (maternal stress, GC exposure and nutrient restriction) on structural and functional brain development and ageing, and on the predisposition for brain-related diseases (early cognitive decline and stroke). The corresponding use of non-human primate cohorts and rodents and transgenic mice offers a truly unique opportunity to translate experimental results to humans.
Determination of BrainAge Each one of us has experienced that perceived (biological) age may notably differ from the numerical age even when features related to ageing such as wrinkles, gray hair or lip height are not accounted for. The same applies for cognitive function or brain atrophy even in the absence of disease. Apart from the question as to why the appearance of ageing is so varied, the foremost issue that concerns us is how to measure brain age. BRAINAGE is a consortium that brings European expertise together to determine biological brain age at a structural, functional and metabolic level. In order to determine the effect of major prenatal stress on brain development and brain ageing, the project aims to develop structural and functional indicators and metabolic, genetic and immune markers of brain ageing. The project employs innovative and standardized techniques (MR morphology, neuropsychology, neurophysiological parameters, blood markers) to measure biological brain age. We identify these indicators and markers in rodents and use non-human primates to translate the use of these markers for the human situation. This will allow us to identify human beings at risk.
Prevention and intervention The goal is to develop preventive measures early in development as well as therapeutic interventions for conditions that are still reversible to support healthy brain ageing in subjects at risk. This goal is based on experimental analyses of the underlying mechanisms via a translational approach in humans, non-human primates, and rodents. We will identify pharmacological interventions that may reverse altered stress sensitivity and vasoreactivity in rodents as a base for preventive or therapeutic human studies.
Ageing and age-related diseases
Efforts towards achieving an increased healthy lifespan have a long history and have inspired mankind over the centuries. In one of the earliest known literary works, the Epic of Gilgamesh, the hero sets out on a long and dangerous journey to search for the secret of eternal life to be found in a plant somewhere at the bottom of an ocean.
Today, in view of the worldwide ageing population, understanding the biology of healthy ageing is more relevant than ever. Healthy brain ageing is a major determinant of quality life-long health, since typical age-associated diseases are brain disorders such as cognitive decline, dementia or stroke. Stroke is the third most common cause for disability and invalidism in Europe. Apart from the element of personal tragedy, this situation also has socioeconomic implications: costs for preventive measures, treatment, rehabilitation as well as care consume 4% of the national health budgets. This figure is expected to rise with increase in life expectancy.
A major goal of the European Community is to find ways to ensure that increase in longevity is also accompanied by an improvement in disease-free life expectancy. The question is how can preventive and therapeutic measures delay the onset of typical age-associated diseases? To answer this question, we need to better understand the roots of health and disease in later life.
Programming of ageing
Human epidemiological and animal studies indicate that in addition to life style and genetic factors, environmental influences in prenatal life have a major impact on brain ageing and age-associated brain disorders.
The first indication that ageing may already start in the womb came from a study performed almost 20 years ago in Hertfordshire which showed that people born small lived shorter lives than people who were born larger. Studies in numerous populations worldwide have since shown that a small size at birth, which serves as a proxy of the suboptimal early life experiences is associated with increased risks of chronic degenerative diseases such as type 2 diabetes, cardiovascular disease, several forms of cancer, chronic obstructive airways disease, osteoporosis and sarcopenia. It was hypothesized that adaptations made by the fetus in response to undernutrition result in permanent changes in physiology and metabolism that later induce chronic degenerative disease. The first direct evidence for this hypothesis in humans has come from the studies by Roseboom’s group showing that prenatal exposure to the Dutch famine may lead to an increased risk for type 2 diabetes, cardiovascular disease, breast cancer, renal and lung diseases.
It is well established now that epigenetic modifications during the fetal period induced by maternal stress, therapies with stress hormones (glucocorticoids) or nutrient restriction have a significant impact on health for the entire duration of an individual’s life. Analysis of this link is the key to identifying preventive and therapeutic procedures. Hence, in the present project, the focus is placed on analyzing the link between human development and brain ageing and age-associated diseases such as cognitive decline and stroke.
Prenatal stressors There is only sparse knowledge available on the effects of the different prenatal stressors on brain structure and function during ageing. Stress sensitivity is programmed prenatally mainly due to maternal stress, stress hormone (glucocorticoid treatment) and nutrient restriction. Many questions on how timing, type, intensity, and duration of environmental disturbances are related to altered neurobehavioral development and early brain ageing still remain unanswered.
Maternal stress during pregnancy Indications that maternal stress results in alteration of cognitive functioning, behavioral and emotional problems are to be had from human cohorts aged up to 30y from van den Bergh's group. Other studies focusing on offspring CNS structures or structure-functioning relationships following maternal stress during pregnancy have shown altered brain function at the neurophysiological level in the newborn and gray matter volume reductions in the 6-9y old offspring at the structural level. The fact that maternal anxiety and stress during human pregnancy is linked with behavior abnormalities during childhood and adolescence, even after controlling for effects of postnatal maternal mood and other relevant prenatal and post-natal confounders, suggests that, as in animal models, a programming effect on the fetal brain had taken place.
Glucocorticoid treatment during pregnancy Almost 10% of all pregnant women threatening preterm delivery are treated with glucocorticoid to enhance fetal lung maturation. This treatment ensures that preterm babies can artificially be ventilated and leads to survival.
Numerous effects of prenatal glucocorticoid treatment at doses used clinically to enhance fetal lung maturation on brain development and brain function during later life were observed in rodents, sheep and non-human primates in the studies from Nathanielsz's and Schwab's groups. In contrast, the effects of prenatal glucocorticoid exposure are much less clear in humans. There is one exception which refers to the few studies that followed-up offspring until the age of 32y and who showed no behavior or neurocognitive abnormalities after one course of prenatal betamethasone. Multiple courses of betamethasone to enhance fetal lung maturation, however, induced abnormalities of functional brain development and behavior disorders between 3 and 6 years of age.
In addition to direct effects of increased stress sensitivity on neuronal activity complex, there is evidence that indirect effects may also play a role. For example, resistance of peripheral glucocorticoid receptors to immunosuppressive GC leads to a pro-inflammatory state that has negative effects on neuronal function.
Nutrient restriction Moderate undernutrition during pregnancy is common in both developing countries and in western societies such as the EU. In industrialized countries, a lifestyle comprising of dieting (including global food reduction) for cosmetic purposes is widespread and is a common cause of moderate undernutrition. A recent study showed that most women do not improve their dietary and lifestyle patterns during pregnancy. Finally, poor fetal nutrition is also present in teenage and in elderly primigravid pregnancies.
Roseboom's group has shown in the Dutch famine cohort and Nathanielsz's and Schwab's groups have shown in non-human primates that maternal malnutrition during pregnancy have effects on cognition that were independent of size and weight at birth. The evidence obtained recently by Roseboom's group from the mid-fifties suggests that cognitive function may also deteriorate faster in those prenatally exposed to the famine in early gestation, but not among those exposed in late gestation. In the British 1946 birth cohort, birth weight was positively associated with cognition in adult age.
Mechanisms of effects of prenatal stress
There is no precise understanding of how prenatal stress induces cognitive disturbances in later life. Both a changed activity of the stress system and a different trajectory of brain development are likely.
Programming of stress sensitivity Stress sensitivity depends on the activity of the stress axis with the two limbs, the autonomous nervous system and the hypothalamo-pituitary adrenal axis. The current (somewhat simplified) concept is that stress sensitivity is programmed prenatally in the last third of gestation when the hypothalamo pituitary adrenal axis matures. If, at this time fetal glucocorticoid concentrations are higher than appropriate for the current stage of maturation, glucocorticoid receptor expression and sensitivity in the hippocampus and hypothalamus, both critical for normal negative feedback to "turn off" the stress response, are permanently reduced by epigenetic modification of the glucocorticoid receptor genes. These mechanistic changes result in hypothalamo pituitary adrenal axis hyperdrive in the presence of glucocorticoid receptor resistance in many animal studies. Importantly, prenatal stress does not only alter activity of the hypothalamo-pituitary adrenal axis permanently, but also changes activity of the second limb of the stress axis, the autonomic nervous system.
Apart from this general mechanism, we do not have a detailed understanding of how the stress axis in later life is altered after prenatal stress. For example, following prenatal stress exposure, human and animal studies show that the HPA axis and the ANS are even less active during certain stages of life. Generally, effects of prenatal stress on stress sensitivity during later life seem to depend on poorly determined conditions such as stress sensitive periods during early life, the amount of stress, and the adversity of the stressor.
Effects of increased stress sensitivity Hypothalamo-pituitary adrenal axis hyperactivity leads to increased stress sensitivity. Increased stress sensitivity contributes to biological ageing through both excessive catecholamine and glucocorticoid secretion and through glucocorticoid receptor resistance. The latter increases the production of pro-inflammatory cytokines, accentuating potential neuronal damage. There are hints that prenatal stress may not only affect brain ageing but also predispose to brain-related diseases. Data from Roseboom's group from the Dutch famine cohort suggest that the cognitive function may deteriorate faster in those subjects who were prenatally exposed to the famine.
Van den Bergh's group is the only group who has tested whether the hypothalamo-pituitary adrenal axis mediates the link between prenatal maternal stress and offspring behavioral problems in humans. It was shown in the 15-year-old offspring that maternal anxiety during weeks 12 to 22 of pregnancy is associated with a high flattened diurnal cortisol profile that shows elevated cortisol secretion in the evening.
Moreover, the interaction of increased stress sensitivity and the serotonergic system may explain the occurrence of depressive disorders since cortisol inhibits this amine system. Indeed, van den Bergh's group has shown an effect of prenatal anxiety on depressed mood that, in part, can be due to a flattened cortisol profile. Depression can impact on the objective age-related cognitive impairment.
Changes in the trajectory of brain development Maternal stress, glucocorticoid treatment and nutrient restriction during pregnancy may also change the trajectory of fetal brain development. Nathanielsz's and Schwab's groups have shown that prenatal glucocorticoid treatment at the clinical dose used to enhance fetal lung maturation affects neurogenesis and myelination in fetal sheep. Studies in rodents clearly show that nutrient restriction alters brain development and cognitive function in later life. Nathanielsz's and Schwab's groups have shown that even moderate maternal undernutrition affects neurogenesis and development of neuronal network formation in the fetal non-human primate. Similarly, abnormalities in brain structure were found in schizophrenic patients exposed to the Dutch famine winter.
Potential targets of intervention
While early intervention is desirable (prevention of stress in the womb), it is also necessary to identify treatment strategies for those individuals who have an increased risk for early brain ageing and age-associated brain disease. Currently, there are millions of people in the EU and all over the world who are already struggling with the effects of prenatal stress on their health. This population also needs targeted interventions.
Bea van den Bergh, PhD
Bea van den Bergh´s group is involved in developmental neuroscience and biological developmental psychology. She is a pioneer in studying the developmental origins of behavior, adding to the efforts of researchers worldwide who are working on the developmental origins of health and disease. Study of the Developmental Origins of Behavior, Health and Diseases (DOBHaD) addresses timely and much needed research issues related to the interface between medical and behavioral sciences. Her DOBHaD research program focuses on physiological and psychological processes and their interplay; thus, contributing to the understanding of mechanisms underlying DOBHaD and enhancing care for infants, children and adolescents with a prenatally acquired vulnerability for behavioural problems, psychopathology or chronic medical conditions. More specific goals are:
To develop instruments or methods that identify infants and children who are at high risk for poor mental and physical health outcomes as soon as possible before or after birth.
To better understand the biological and behavioral mechanisms that can explain enhanced vulnerability.
To test and implement biomedical and behavioral interventions that are successful at preventing disease or disorder onset, improving prognosis and enhancing quality of life.
Christian Gaser, PhD
Christian Gaser leads the group on Structural Brain Mapping at the Dept. of Neurology. He has substantial experience to plan, perform, and lead independent and internationally distributed research projects. This is particularly documented by the achievements of his Independent Junior Research Group ”Neuroimaging” which has contributed to scientific progress in a wide range of topics in neuroscience, often working across field boundaries. His research group is supported by the Federal Ministry of Education and Research (BMBF) to develop and apply methods for patient classification using computational morphometry. He has carried out a great amount of work in the field of neuroimaging with a specific focus on the development of valuable analysis methods for structural brain data. Amongst these methods, he has developed and implemented the VBM (voxel-based morphometry) toolboxes as an extension to the algorithms used by SPM8 (Wellcome Department of Cognitive Neurology), the software package that is the central processing software for MR morphometry of this project. In addition, he has pioneered the analysis of use-dependent plasticity. Furthermore, he uses state-of-the-art techniques to assess the stage of age progression by estimating the individual BrainAGE scores with applications for the early detection of Alzheimer’s disease.
Guido Krebiehl, PhD
Biocrates is a leading biotech company in the field of metabolic biomarker research and kit development. Using a targeted, mass spectrometry-based metabolomics approach, Biocrates identifies and quantifies endogenous metabolites in body fluid or tissue samples and develops them into powerful biomarkers. Biocrates has a strong background in biological sciences and (bio-) informatics as well as long-standing experience in analytical method development, method application, data analysis, and project management. Biocrates is well equipped with a state-of-the-art mass spectrometry platform that, in combination with its comprehensive methodological knowledge, allows the accurate quantification of a vast range of metabolites across several biochemical classes in a targeted metabolomics approach. Biocrates has been involved in various international and national research consortia and by applying its analytical services, directly contributed to neonatal research projects like e.g. the EU-funded NEOBRAIN project.
Peter W. Nathanielsz, MD PhD
Dr. Peter Nathanielsz, formerly director of the Center for Pregnancy and Newborn Research at the University of Texas Health Sciences Center, is now the Distinguished Research Professor of Life Course Studies within the UW College of Agriculture and Natural Resources´ Department of Animal Science.
Peter W. Nathanielsz has researched fetal development for over forty years and was recently named as one of the top 5% of funded NIH investigators in the United States. For his work on fetal development he has been made a Fellow ad Eundem of the Royal College of Obstetricians in England. He delivered the 2011 Messenger Lectures at Cornell University, that university’s highest scientific recognition. He wrote the first book for the general reader on Developmental Programming entitled Life in the Womb: The origin of health and disease, published in 1999.
The group is the only one in the world owning adult non-human primate cohorts that were prospectively exposed to different prenatal stressors (glucocorticoid exposure and nutrient restriction) and are dedicated to study Developmental Programming of Health and Disease in later life.
Matthias Platzer, PhD
His mission is to understand the molecular mechanisms that underlie the ageing process and that lead to age-related diseases with the hope that eventually this knowledge can contribute to a more healthy ageing of the human population. Cooperating with clinical partners, the group is involved in detection and functional analyses of genetic & epigenetic variations that determine the individual susceptibility to complex disorders (inflammation, obesity, cancer) and ageing. They are also engaged in the sequence analysis of eukaryotic model organisms, prokaryotic genomes and metagenomes. The group is one of the first laboratories in Germany applying next-generation sequencing for genome and transcriptome analysis.
Juan Camilo Estrada Rodríguez, PhD
Dr. Juan Camilo Estrada received his Bachelor in Biochemistry from the Autonomous University of Madrid. He earned his Ph.D. in Molecular Biology at the prestigious National Center for Cardiovascular Diseases (CNIC). During his Ph.D. program he focused in the study of oxidative stress on genetic stability and biosafety of human stem cells for his therapeutic application. After his doctorate, he specialized in the study of non-canonical activity of telomerase in the cell metabolism and senescence. His works has allowed him to participate in various international conferences and publish several scientific articles in the arena of regenerative medicine and ageing, and develop a patent to identifying new genetic and transcriptional biomarkers of cellular senescence in culture. Dr. Estrada has extensive experience in the field of human molecular cytogenetic with strong handling of different probes (PNA, CEP and LSI) for the chromosome labeling by classic fluorescence in situ hybridization (FISH) and derived techniques as multicolor FISH (M-FISH) and quantitative FISH (Q-FISH).
Tessa J. Roseboom, PhD
The AMC is one of the most prominent medical centers in the Netherlands with a leading position in medical research, both nationally and internationally. Tessa Roseboom is one of the AMC´s Principal Investigators leading the Fetal Origins Research group within the Academic Medical Center. She obtained funding from the Dutch Heart Foundation, the Netherlands Organisation for Scientific Resaerch, The European Science Foundation (Eurostress Program), Medical Resaerch Courncil and the Diabetes Fund with a volume of nearly 1 million Euros. She established the healthy WOMB study center to investigate the role of various influences during early human development on later health.
She has long standing experience in studying the early origins of later disease. She has worked on the Dutch famine birth cohort study for the past 15 years, and has led that study during the past 10 years. This cohort consists of 2.414 singletons who were born around the time of the Dutch famine in 1944-45. The cohort has been followed up extensively, focussing not only on metabolic and cardiovascular disease, but also on psychiatric diseases, infections, wellbeing, and certain types of cancer. She was the first to demonstrate that undernutrition during gestation in humans is associated with a doubled rate of heart disease, and of late, she also found suggestions of earlier brain ageing. She has been involved in investigateing research into gene environmental interactions, transgenerational effects, and outcome on reproductive succcess and epigenetic mechanisms.
Matthias Schwab, MD
Matthias Schwab is a trained pathophysiologist and neurologist. He is a senior member of the Department of Neurology and Head of the Research Group 'Fetal Brain Development and Programming of Diseases in Later Life' for more than 15y and strongly committed to the link between human development and ageing. His focus is on fetal brain development and the programming of brain-related disorders with a strong emphasis on stress effects and inflammation. He represents one of the first scientist who dealt with effects of prenatal glucocorticoid exposure on the brain using large animal models. He has a long-standing and successful cooperation with many partners in Europe and worldwide which have resulted in many joint publications. Prof. Schwab is head of the interdisciplinary sleep research unit with focus on autonomous and vascular dysregulation during prenatal development of sleep and during ageing. He has developed innovative nonlinear methods of EEG analysis.
Jan Tuckermann, PhD
Jan Tuckermann and his group’s aim is the deeper understanding of the action of GCs via their nuclear receptor (GR) in age-related processes. They use a combinatorial approach employing functional characterization of mouse strains conditionally mutated both in the GR and selected target genes in disease models, together with the development of functional screening tools for relevant cell types in age-related disorders. Here the goal is to decipher new mechanisms and to identify new mediators of therapeutic and side effects of GCs. Thus, by understanding GC-mediated effects in organs and tissues, knowledge about about degenerative processes during ageing can be acquired.
Prof. Dr. med. Matthias Schwab
Klinik für Neurologie,
Leiter des Multiple Sklerose Zentrums Leiter des interdisziplinären Zentrums für Schlaf und Beatmungsmedizin
Telefon: +49 3641 9-323411
Fax: +49 3641 9-323412 Web
(Genetisch modifizierte) Nagermodelle
pränatale und postnatale Stressmodelle und Modelle der fetalen Fehlernährung
Telemedizinische Ableitung von (neuro)physiologischen Parametern
MRT-basierte Untersuchung der strukturellen Hirnentwicklung – und alterung mit Bestimmung des biologischen Hirnalters im Vergleich zum chronologischen Alter
small vessel myography
Messung der Glukokortikoidrezeptor- und Stresssensitivität
Bestimmung von Zytokinen und des Metaboloms
immunhistochemische und molekularbiologische (z.B. Western Blot) Darstellung von Markern der Hirnentwicklung – und alterung
Chronisch instrumentiertes fetales Schaf
pränatale Stressmodelle und Modelle der fetalen Fehlernährung
Intrauterine Hirndurchblutungsmessung mit Mikrosphären und Laser-Doppler-Flowmetrie
Nutzung von Herzfrequenzvariabilitätsparametern, AEP und SEP sowie innovativer linearer und nichtlinearer EEG-Analysemethoden zur Untersuchung der Reifung komplexer neuronaler Interaktionen und der Kopplung von autonomen und kortikalen Rhythmen
small vessel myography
Hypoxiemodelle (repetitive Nabelschnurokklusion und hypoxische Hypoxie)
Untersuchungen an Kohorten mit Exposition zu fetaler Fehlernährung oder Stress
Untersuchung der Hirnentwicklung und -alterung mit innovativen Methoden zur Bestimmung der kognitiven Funktion und Hirnaktivität (EEG, MEG)
Messung der Glukokortikoidrezeptor- und Stresssensitivität
Bestimmung von Zytokinen und des Metaboloms
MRT-basierte Untersuchung der strukturellen Hirnentwicklung und Bestimmung des biologischen Hirnalters im Vergleich zum chronologischen Alter
Original papers in peer reviewed journals
Hermes M, Antonow-Schlorke I, Hollstein D, Kühn S, Rakers F, Frauendorf V, Dreiling M, Rupprecht S, Schubert H, Witte OW, Schwab M (2020). Maternal psychosocial stress during early gestation impairs fetal structural brain development in sheep. Stress 23(2):233-242.
Schwab M, Witte OW. Prenatal stress and brain disorders in later life. (2020). Neurosci Biobehav Rev. 2020 Jun 16:S0149-7634(20)30429-2. doi: 10.1016/j.neubiorev.2020.06.002.
Franke K, Bublak P, Hoyer D, Billiet T, Gaser C, Witte OW, Schwab, M (2020). In vivo biomarkers of structural and functional brain development and ageing. Neurosci Biobehav Rev in press.
Franke K, Van den Bergh BRH, Rakers F, Kroegel N, de Rooij SR, Roseboom TJ, Witte OW, Nathanielsz, PW Schwab, M (2020). Effects of Malnutrition and Maternal Stress during Pregnancy on Offspring Brain Structure in Humans. Neurosci Biobehav Rev 2020 Jan 28:S0149-7634(17)30748-0. doi: 10.1016/j.neubiorev.2020.01.031.
Müller JJ, Antonow-Schlorke I, Kroegel N, Rupprecht S, Rakers F, Witte OW, Schwab M (2018). Cardiovascular effects of prenatal stress – Are there implications for cerebrovascular, cognitive and mental health outcome? Neurosci Biobehav Rev in press.
Van den Bergh B.R.H., van den Heuvel MI., Lahti M., Braeken M., de Rooij S.R., Entringer S., Hoyer D., Roseboom T., Räikkönen K., King S., Schwab M. (2018). Prenatal developmental origins of behavior and mental health: The influence of maternal stress in pregnancy. Neurosci Biobehav Rev Jul 28. pii: S0149-7634(16)30734-5. [Epub ahead of print].
Rakers F, Rupprecht S, Dreiling M, Bergmeier C, Witte OW, Schwab M (2017). Transfer of maternal psychosocial stress to the fetus. Neurosci Biobehav Rev doi: 10.1016/j.neubiorev.2017.02.019. [Epub ahead of print].
Sahm A, Bens M, Henning Y, Vole C, Groth M, Schwab M, Platzer M, Szafranski K, Dammann P (2018). Higher transcriptome 1 stability during 2 aging in long-lived giant mole-rats 3 compared to short-lived rats. Aging-US 10(12):3938-56.
Schiffner R, Bischoff S, Schubert H, Rakers F, Rupprecht S, Maziolis G, Huber O, Lemke C, Rupprecht S (2018). Schwab M, Lehmann T, Schmidt M. Underlying mechanism of subcortical brain protection during hypoxia and reoxygenation in a sheep model - influence of α1-adrenergic signaling. PLoS one 13(5):e0196363.
Sahm A, Bens M, Szafranski K, Holtze S, Groth M, Görlach M, Calkhoven C, Müller C, Kaether C, Schwab M, Cellerino A, Hildebrandt T, Burda H, Dammann P, Platzer M. (2018). Long-lived rodents reveal signatures of positive selection in genes associated with lifespan and eusociality. PLoS Genet 14(3):e1007272.
Dreiling M, Schiffner R, Bischoff S, Rupprecht S, Kroegel N, Schubert H, Witte OW, Schwab M, Rakers F (2018). Impact of chronic maternal stress during early gestation on maternal-fetal stress transfer and fetal stress sensitivity in sheep. Stress 21 (1):1-10.
Franke K, Gaser C, Roseboom TJ, Schwab M, de Rooij SR (2017). Premature brain aging in humans exposed to maternal nutrient restriction during early gestation. Neuroimage 173:460-71.
Franke K, Clarke GD, Dahnke R, Gaser C, Kuo AH, Li C, Schwab M, Nathanielsz PW (2017). Premature brain aging in baboons resulting from moderate fetal undernutrition. Front Aging Neurosci 9:92.
Agba OB, Lausser L, Huse K, Bergmeier C, Jahn N, Groth M, Bens M, Gall M, Witte OW, Kestler H, Schwab M, Platzer M (2017). Tissue-, sex- and age-specific DNA methylation of rat glucocorticoid receptor gene promoter and insulin like growth factor 2 imprinting control region. Physiol Genomics 49(11):690-702.
Kuo AH, Li C, Huber HF, Schwab M, Nathanielsz PW, Clarke GD (2017). Maternal nutrient restriction during pregnancy and lactation leads to impaired right ventricular function in young adult baboons. J Physiol 595(13):4245-4260.
Kuo AH, Li J, Li C, Huber H, Schwab M, Nathanielsz PW, Clarke G (2017). Prenatal steroid administration leads to adult pericardial and hepatic steatosis in male baboons. Int J Obesity (Lond). 2017 Aug;41(8):1299-1302.
Müller JJ, Schwab M Rosenfeld CR, Antonow-Schlorke I, Nathanielsz PW, Rakers F, Schubert, H, Witte OW, Rupprecht S (2017). Fetal sheep mesenteric resistance arteries in sheep: functional and structural maturation. J Vasc Res 54(5):259-271.
Schiffner R, Rodríguez-González GL, Rakers F, Nistor M, Nathanielsz PW, Daneva T, Schwab M, Lehmann T, Schmidt M (2017). Effects of late gestational fetal exposure to dexamethasone administration on the postnatal hypothalamus-pituitary-adrenal axis response to hypoglycemia in pigs. Int J Mol Sci 18(11). pii: E2241.
Schiffner R., Bischoff S.J., Lehmann T., Rakers F., Rupprecht S., Reiche J., Matziolis G., Schubert H., Schwab M., Huber O., Schmidt M (2017). Redistribution of cerebral blood flow during severe hypovolemia and reperfusion in a sheep model: critical role of α1-adrenergic signaling. Int J Mol Sci 18(5). pii: E1031.
Anegroaie P, Frasch MG, Rupprecht S, Antonow-Schlorke I, Müller T, Schubert H, Witte OW, Schwab M (2017). Development of somatosensory-evoked potentials in foetal sheep: effects of betamethasone. Acta Physiol (Oxf) 220(1):137-49.
Bischoff SJ, Schmidt M, Lehmann T, Irintchev A, Schubert H, Jung C, Schwab M, Huber O, Matziolis G, Schiffner R (2016). Increase of cortical cerebral blood flow and further cerebral microcirculatory effects of Serelaxin in a sheep model. Am J Physiol Heart Circ Physiol 311(3):H613-20.
de Rooij SR, Caan MW, Swaab DF, Nederveen AJ, Majoie CB, Schwab M, Painter RC, Roseboom TJ (2016). Prenatal famine exposure has sex-specific effects on brain size. Brain 139(Pt 8):2136-42.
Dreiling M, Bischoff S, Schiffner R, Rupprecht S, Kiehntopf M, Schubert H, Witte OW, Nathanielsz PW, Schwab M, Rakers F (2016). Stress-induced decrease of uterine blood flow in sheep is mediated by alpha 1-adrenergic receptors. Stress 19 (5):547-51.
Rakers, F, Schiffner, R, Brandstädt, A, Rupprecht, S, Witte, OW, Schlattmann, P, Schwab, M (2016). Rapid weather changes are associated with increased ischemic stroke risk: a case-crossover study. Eur J Epidemiol 31(2), 137-146.
Bischoff SJ, Schmidt M, Lehmann T, Schwab M, Matziolis G, Saemann A, Schiffner R (2015). Renal glucose release during hypoglycemia is partly controlled by sympathetic nerves - a study in pigs with unilateral surgically denervated kidneys. Physiol Rep 3(11):pii: e12603.
de Rooij, SR, van Pelt AAM, Ozanne SE, Korver CM, van Daalen SK, Painter RC, Schwab M, Viegas MH:, Roseboom TJ (2015). Prenatal undernutrition and leukocyte telomere length in late adulthood: the Dutch famine birth cohort study. Am J Clin Nutr 102(3):655-60.
Rakers F, Bischoff S, Schiffner, R, Haase M, Rupprecht S Kiehntopf M, Kühn-Velten WN, Schubert H, Witte OW, Nijland MJ, Nathanielsz PW, Schwab, M (2015). Role of Catecholamines in Maternal-Fetal Stress Transfer in Sheep Fetus. Am J Obstet Gynecol 213(5):684.e1-9.
Xie L, Antonow-Schlorke I, Schwab M, McDonald, TJ, Nathanielsz PW (2013). The frontal cortex IGF system is down regulated in the term, intrauterine growth restricted fetal baboon. Growth Horm IGF Res 23(5):187-92.
Rakers F, Frauendorf V, Rupprecht S, Schiffner R, Bischoff S, Kientopf, M, Reinhold P, Witte OW, Schubert H, Schwab, M (2013). Effects of early and late-gestational maternal stress and synthetic glucocorticoids on development of the fetal hypothalamic–pituitary–adrenal axis in sheep. Stress 16:122-9.
Schwab M, Coksaygan T, Rakers F, Nathanielsz PW (2012). Glucocorticoid exposure of sheep at 0.7 to 0.75 gestation augments late gestation fetal stress responses. Am J Obstet Gynecol 206(3):253.e16-22.
Antonow-Schlorke I1, Schwab M1, Cox LA, Li C, Stuchlik K, Witte OW, Nathanielsz PW, McDonald TJ (2011). Vulnerability of the fetal primate brain to moderate reduction in maternal global nutrient availability. PNAS 108(7):3011-6 (1authors contributed equally to the paper).
Schneider U, Arnscheidt C, Schwab M, Haueisen J, Seewald, HJ Schleussner, E (2010). Steroids that induce lung maturation acutely affect higher cortical function: a fetal magnetoencephalography study. Reprod Sci 18(1):99-106
Löhle M, Schwab M, Kadner S, Ford S, Nijland M, Lawrence P, Gilbert J, Brenna T, Nathanielsz PW (2009). Dose response effects of betamethasone on maturation of the fetal sheep fetal lung. Am J Obstet Gynecol 202(2):186.e1-7.
Frasch MG, Müller T, Szynkaruk M, Schwab M (2009). Validation of spontaneous assessment of baroreceptor reflex sensitivity and its relation to heart rate variability in the ovine fetus pre- and near-term. Can J Physiol Pharmacol l87(9):736-42.
Schwab K, Groh T, Schwab M, Witte H (2009). Nonlinear analysis and modeling of cortical activation and deactivation patterns in the immature fetal electrocorticogram. Chaos 19(1):015111.
Frasch MG, Müller T, Hoyer D, Weiss C, W Schubert H, Schwab M (2009). Nonlinear properties of vagal and sympathetic modulations of heart rate variability in ovine fetus near term. Am J Physiol 296(3):R702-7.
Frasch MG, Müller T, Wicher C, Weiss C, W Schwab K, Schubert H, Schwab M (2009). Heart rate variability analysis allows early asphyxia detection in ovine fetus. Reprod Sci 16(5):509-17.
Antonow-Schlorke I, Helgert A, Gey C, Coksaygen T, Schubert H, Nathanielsz PW, Witte OW, Schwab M (2009). Adverse effects of antenatal glucocorticoids on cerebral myelination in sheep are dose dependent and specific to the fetal stage of development. Obstet Gynecol 113(1):142-151.
Raschke C, Schmidt S, Schwab M, Jirikowski G (2008). Effects of betamethasone treatment on central myelination in fetal sheep: an electron microscopical study. Anat Histol Embryol 37:95-100.
McCallum J, Smith N, Schwab M, Nathanielsz PW, Coksaygan T, Reinhardt B, Richardson B (2008). Effects of antenatal glucocorticoids on cerebral substrate metabolism in the pre-term ovine fetus. Am J Obstet Gynecol 198:105.e1-9.
McCallum J, Smith N, MacLachlan JN, Coksaygan T, Schwab M, Nathanielsz PW, Richardson B (2008). Effects of antenatal glucocorticoids on cerebral protein synthesis in the pre-term ovine fetus. Am J Obstet Gynecol 198:103.e1-6.
Antonow-Schlorke I, Müller T, Brodhun M, Wicher C, Schubert H, Nathanielsz PW, Witte OW, Schwab M (2007). Betamethasone related acute alterations of microtubule associated proteins in the fetal sheep brain are reversible and independent of age during the last third of gestation. Am J Obstet Gynecol 196:553.e1-6. (“Editors choice”)
Frasch MG, Müller T, Wicher C, Weiss C, W Löhle M, Schwab K, Schubert H, Nathanielsz, PW, Witte OW, Schwab M (2007). Fetal body weight and the development of the control of the cardiovascular system in fetal sheep. J Physiol (Lond) 579:893-907
Antonow-Schlorke I, Ebert M, Cun L, Gschanes A, Witte OW, Nathanielsz PW, Schwab M (2007). Effects of antenatal glucocorticoid therapy on glucose transporter proteins in the fetal baboon brain. J Med Primatol 36:17-20.
Frank B, Frasch MG, Schneider U, Roedel M, Schwab M, Hoyer D. (2006) Complexity of heart rate fluctuations in near-term sheep and human fetuses during sleep. Biomed Tech (Berl). 51:233-6.
Schwab M, Coksaygan T, Samtani M, Jusko WJ, Nathanielsz PW (2006). Kinetics of betamethasone and fetal cardiovascular adverse effects in pregnant sheep after different doses. Obstet Gynecol 108:617-25.
Antonow-Schlorke I, Ebert M, Müller T, Coksaygan T, Schubert H, Gschanes A, Witte OW, Nathanielsz PW, Schwab M (2006). Glucocorticoid effects on glucose transporter proteins in the fetal sheep brain. Neurosci Lett 403(3):261-265.
Schwab M, Coksaygan T, Nathanielsz PW (2006). Betamethasone effects on ovine uterine and umbilical placental perfusion at the dose used to enhance fetal lung maturation. Am J Obstet Gynecol 194:572-579.
Löhle M, Müller T, Wicher C, Roedel M, Schubert H, Nathanielsz PW, Witte OW, Schwab M (2005). Betamethasone effects on fetal sheep cerebral blood flow are not dependent on maturation of cerebrovascular system and pituitary-adrenal axis. J Physiol (Lond) 564:575-588. Samtani MN, Schwab M, Nathanielsz PW, Jusko WJ (2004). Area/moment and compartmental modeling of pharmacokinetics during pregnancy: applications to maternal/fetal exposures to corticosteroids in sheep and rats. Pharm Res 21:2279-2292.
Colberg C, Antonow-Schlorke I, Müller T, Schubert H, Nathanielsz PW, Witte OW, Schwab M (2004). Recovery of glucocorticoid-related loss of synaptic density in the fetal sheep brain at 0.75 of gestation. Neurosci Lett 364:130-134.
Samtani MN, Schwab M, Nathanielsz PW, Jusko WJ (2004). Stabilization and HPLC analysis of betamethasone sodium phosphate in plasma. J Pharm Sci 93: 726-732.
Antonow-Schlorke I, Schwab M, Li C, Nathanielsz PW (2003). Glucocorticoid exposure at the dose used clinically alters cytoskeletal proteins and presynaptic terminals in the fetal baboon brain. J Physiol (Lond) 547: 117-123. (Artikel erhielt Titelblatt des Journals).
Müller T, Schubert H, Schwab M (2003). Early prediction of fetal numbers in sheep based on peripheral plasma progesterone concentrations and season of the year. Vet Rec 152:137-8.
Müller T, Löhle M, Schubert H, Wicher C, Antonow-Schlorke I, Sliwka U, Nathanielsz PW, Schwab M (2002). Developmental changes in cerebral autoregulatory capacity in the fetal sheep parietal cortex. J Physiol (Lond) 539: 957-67.
Schwab M, Rödel M, Schmidt K, Müller T, Schubert H, Anwar M A, Nathanielsz PW (2001). Nonlinear changes of electrocortical activity after antenatal betamethasone treatment in fetal sheep. J Physiol (Lond) 531: 535-543.
Schwab M, Antonow-Schlorke I, Kühn B, Müller T, Schubert H, Walter B, Sliwka U, Nathanielsz PW (2001). Effect of antenatal betamethasone treatment on microtubule associated proteins MAP1B and MAP2 in fetal sheep. J Physiol (Lond) 530: 497-506. (Artikel erhielt Titelblatt des Journals).
Antonow-Schlorke I, Kühn B, Müller T, Schubert H, Sliwka U, Nathanielsz P W, Schwab M (2001). Antenatal betamethasone treatment reduces synaptophysin in presynaptic terminals in the fetal sheep brain. Neurosci Lett 297: 147-150.
Schwab M, Rödel M, Anwar M A, Buchwalder LF, Müller T, Schubert H, Walter B, Nathanielsz PW (2000). Effects of betamethasone administration to the fetal sheep in late gestation on fetal cerebral blood flow. J Physiol (Lond) 528: 619-632.
Schmidt K, Kott M, Müller T, Schubert H, Schwab M (2000). Developmental changes in the complexity of the electrocortical activity in fetal sheep. J Physiol (Paris) 94: 435-443.
Schwab M, Schmidt K, Witte H, Abrams RM (2000). Investigation of nonlinear ECoG changes during spontaneous sleep state changes and cortical arousal in fetal sheep. Cereb Cortex 10: 142-148.
Schmidt K, Schwab M, Abrams RM, Witte H (1999). Nonlinear analysis of the fetal ECoG: predictability and bispectral measures. Theor Biosci 118: 219-230.
Witte H, Breidbach O, Schmidt K, Schwab M (1999). News and views in signal analysis of the electröncephalogram (EEG). Theor Biosci 118: 284-299.
Anwar MA, Schwab M, Poston L, Nathanielsz PW (1999). Betamethasone mediated vascular dysfunction and changes in hematological profile in the ovine fetus. Am J Physiol 276: H1137-1143.
Schwab M, Antonow-Schlorke I, Zwiener U, Bauer R (1998). Brain derived peptides reduce the size of cerebral infarction and loss of MAP2 after focal ischemia in rats. J Neural Transmiss Suppl. 53: 299-311.
Antonelli P, Abrams RM, Gerhardt KJ, Schwab M, Bauer R (1998). Vestibular function of the fetal sheep. Otolaryngol Head Neck Surg 118: 571-575.
Abrams RM, Schwab M, Gerhardt KJ, Bauer R, Antonelli P (1998). Caloric stimulation of the inner ear in fetal sheep: Effect on eye movements and electrocorticogram. Int J Ped Otorhinolaryngol 45: 59-68.
Schwab M, Bauer R, Zwiener U (1998). Mild hypothermia prevents the occurrence of cytotoxic brain edema in rats. Acta Neurobiol Exp 58: 29-35.
Schwab M, Bauer R, Zwiener U (1997). The distribution of normal brain water content in wistar rats and its increase due to ischemia. Brain Res 749: 82-87.
Schwab M, Schaller R, Bauer R, Zwiener U (1997). Morphofunctional effects of permanent bilateral carotid occlusion and short-term hypoxia in rats. Exp Tox Pathol 49: 29-37.
Schwab M, Bauer R, Zwiener U (1997). Physiological effects and brain protection by hypothermia and Cerebrolysin after permanent bilateral carotid artery clamping in rats. Exp Tox Pathol 49: 105-116.
Bauer R, Schwab M, Abrams RM, Stein J, Gerhardt KJ (1997). Electrocortical and heart rate response during vibroacoustic stimulation in fetal sheep. Am J Obstet Gynecol 177: 66-71.
Schwab M, Antonow-Schlorke I, Dürer U, Bauer R (1996). Effects of Cerebrolysin on cytoskeletal proteins after focal ischemia in rats. J Neural Transmission Suppl 47: 279.
Abrams RM, Schwab M, Gerhardt KJ, Bauer R, Peters AJM (1996). Vibroacoustic stimulation with a complex signal: Effect on behavioral state in fetal sheep. Biol Neonate 70: 155-164