Up to 20 percent of children and adolescents in Germany suffer from a mental disorder. However, not all children are equally at risk. At the German Center for Mental Health (DZPG), research is being conducted on many projects specifically for groups affected by risk factors aiming for earlier diagnosis and a broad network of prevention and support services for all ages.

Prof. Dr. Peter Falkai, Director of the Department of Psychiatry and Psychotherapy at the LMU Clinic and spokesperson for the Munich DZPG partner site, emphasizes: "Mental illness is one of the most relevant health problems in Germany. Some children and adolescents can be protected with preventive measures. This is what the DZPG is committed to with its translational research.”

Anxiety, hyperkinetic syndrome, learning disabilities, depression, addictions, and eating disorders: The list of mental disorders affecting children and adolescents is long. If left unaddressed during childhood and adolescence, mental health problems often carry over into adulthood. "One in five children and adolescents is affected by mental disorders," says Falkai. "In adults, the figure rises to one in four. This makes mental illness one of the greatest challenges in medicine.”

Growing up as a risk factor: The risk of mental illness increases with age

As they grow older, adolescents are exposed to stress as they finish school, begin a professional career, form their own social networks, and find social roles. Nevertheless, the risk of mental illness is not only due to the maturation process. Research at the DZPG focuses on specific risk factors. Falkai explains: "The number of mental disorders in children and adolescents increased significantly during the coronavirus pandemic, with contact restrictions, loneliness, and higher levels of domestic violence". The increase is confirmed by a study conducted by the BKK umbrella organization on behalf of the Children's Health Foundation. It shows that in the pandemic years 2020 and 2021, 15-19-year-old female policyholders in particular suffered from psychological symptoms. Anxiety and adjustment disorders were observed at above-average rates. And the next crisis is already here: "We are also observing an increase in post-traumatic stress disorder and depression due to external stressors such as armed conflicts.”

Prevention before treatment

"Many of the DZPG's research projects are aimed at prevention," says Prof. Falkai. "Many mental disorders develop their first symptoms even before they become manifest. In practice, these first external signs are often unspecific: "They include sleep disturbances, inner restlessness, and physical complaints such as stomach aches, headaches, and back pain. Eventually, this development can lead seamlessly to anxiety disorders. A deterioration in concentration and therefore in school performance is also frequently observed. Experts are registering increasing numbers of cases in such areas as well:  Among schoolchildren, potentially psychosomatic complaints such as headaches, stomachaches, and backaches, as well as problems falling asleep and depression, have increased significantly over the years. That's one of the findings of WHO's Health Behavior in School-aged Children (HBSC) study.

Preventing mental disorders in young people

The DZPG's research on primary prevention is aimed at this early stage: the goal is to reduce the likelihood that children and adolescents will develop mental disorders. Prof. Dr. Andreas Meyer-Lindenberg, Director of the Central Institute for Mental Health in Mannheim and spokesperson for the DZPG, explains: "The first step is to measure mental health at all. The DZPG is currently carrying out such a measurement in Bochum with the German Health Barometer. A representative sample of the population is regularly asked about their mental health. This makes it possible to measure changes in the mental health of the population - for example, during an economic crisis or a pandemic - so that measures can be taken to prevent a collapse.

Research for children at risk

The risk of mental illness is not the same for all children and adolescents in Germany: "We know risk factors that can trigger or exacerbate mental illness. Premature birth is one of them," says Falkai. This is the focus of the DZPG site in Tübingen. As part of an early detection program, the families of premature babies are closely monitored in order to identify possible early symptoms of mental illness and to reduce the family stress caused by the premature birth. At the same time, a large cohort of twins is being followed to understand risk and resilience factors, identify early symptoms and offer intervention options.

However, risks also arise in the further course of the disease. Prof. Dr. Dr. Andreas Heinz, Director of the Department of Psychiatry and Psychotherapy CCM at the Charité - Universitätsmedizin Berlin and spokesperson for the DZPG: "One factor is socio-economic status, particularly with regard to barriers to access to health care, but also mental health literacy: How much do I know about mental health? Growing up in an urban area and having one or both parents unemployed are also risk factors for mental disorders. Minority status is another risk factor. For this reason, the DZPG launched a project in the Wattenscheid district of Bochum. An above-average number of people there live in precarious circumstances, have a migration background, or are affected by unemployment. Under the motto "Urban Mental Health" (UMH), the Research and Treatment Center for Mental Health (FBZ) at the Ruhr University Bochum is developing a novel prevention concept. For the first time, it brings together science, policy, and practice to improve the mental health of children and adolescents. The project aims to improve the mental health of teachers by increasing their resilience, and to develop a curriculum for students to improve their mental health literacy. If successful, it could become a blueprint for the whole of Germany.

Mental health problems of parents as a risk factor

Researchers at the FU Berlin are focusing on children of parents who have difficulty dealing with their children because of their own mental stress. This can mean, for example, that one or more parents suffer from a mental illness (e.g. depression or anxiety disorders) or have limited social or financial resources. Research shows that such stressors can be associated with increased parental stress, which in turn can make it more difficult to communicate and interact with one's children. An app is being developed as a low-threshold way for parents to strengthen their own mental health and promote positive parenting behaviors.

Earlier diagnosis for a better start in adulthood

The DZPG is also conducting research into secondary prevention, i.e. improving the chances of treatment by detecting diseases at an early stage. Falkai: "The DZPG is currently evaluating centers for the early detection and initial treatment of mental illnesses and wants to improve the information available to the public. The goal is for children, adolescents and their families to have access to competent early detection centers that specialize in mental disorders. "Only experts can distinguish symptoms that indicate a mental illness from those that are part of normal maturation and development processes.”

References: Kindergesundheitsbericht 2023 der Child Health Foundation;  Health Behavior in School-aged Children (HBSC)-Studie, WHO

Source: DZPG

Teams from the Medical Faculty of Heidelberg University, the European Molecular Biology Laboratory (EMBL) Heidelberg, the German Cancer Research Center (DKFZ), and Leiden University have shown in mice that certain immune cells keep lung tumors in check if they have previously been treated with iron nanoparticles. The recently published work was funded by the Translational Lung Research Center Heidelberg, a partner of the German Center for Lung Research.

Certain immune cells, known as macrophages, are attracted to tumors and can attack them - or protect them from other immune cells and chemotherapy. Introducing iron particles can reliably steer the macrophage behavior towards cancer defense. This discovery was made by a team led by Professor Martina Muckenthaler, Medical Faculty Heidelberg, University of Heidelberg, and group leader at the Molecular Medicine Partnership Unit (MMPU), a cooperation between the Medical Faculty Heidelberg and EMBL Heidelberg. The scientists investigated a form of non-small cell lung carcinoma that initially responds well to targeted drugs, but becomes resistant over time and grows back. In mice suffering from this type of lung cancer, specially prepared iron nanoparticles were able to slow tumor regrowth, as the team recently reported in the journal ACS Nano. How long this effect lasts and whether it is transferrable to humans cannot yet be determined from these results. Nevertheless, the team believes that this novel immunotherapy has the potential to enhance the effects of current therapies.

The research was conducted in collaboration with the groups of Prof. Dr. Rocio Sotillo, Director of the Division of Molecular Basis of Thoracic Tumors at DKFZ, Prof. Dr. Matthias W. Hentze, Director of EMBL, and Prof. Dr. Matthias Barz, Director of the Department of BioTherapeutics at the Leiden Academic Centre for Drug Research (LACDR), University of Leiden, Netherlands. The lead authors are former doctoral students Natalie K. Horvat, MMPU, and Sara Chocarro, DKFZ.

Iron makes macrophages aggressive

The idea of an iron booster for immune cells came from observations in a completely different disease affecting the blood: When deformed red blood cells are broken down in hereditary sickle cell anemia, the iron contained within them enters the blood and tissues. "When macrophages in the liver absorb this iron, they attack surrounding liver cells and cause tissue damage," says Professor Muckenthaler, who investigates various disorders of iron metabolism at the Center for Translational Biomedical Iron Metabolism Research at Heidelberg University Hospital. "As red blood cells are also broken down in the tumor environment, we took a closer look at the tumor microenvironment."

Lung tumors stimulate the growth of blood vessels in their surroundings in order to be better supplied with oxygen and nutrients. From these blood vessels, red blood cells enter the often inflamed tissue and are broken down by macrophages. Their iron accumulates in the macrophages. In tissue samples from patients with non-small cell lung carcinoma (NSCLC), the team previously found that if such an "iron curtain" is present around the tumor, the tumors remain smaller and patients have a better prognosis than those without iron accumulation. "The macrophages in the vicinity of the tumors are more aggressive against cancer. We wanted to take advantage of this natural activation of cancer defense," the scientist explains.

The team administered specially prepared iron nanoparticles from Professor Barz's laboratory to mice suffering from a subtype of human lung tumors, so-called ALK-positive NSCLCs, via the respiratory tract. The animals had initially been treated with the common tumor drug crizotinib, which precisely targets an altered protein of this type of cancer and temporarily suppresses the tumors completely. "Targeted drugs such as Crizotinib are a major advance in the treatment of this specific type of cancer. Unfortunately, the tumors become resistant after an average of 19 months. If we were able to additionally activate the immune system with the iron booster, we could potentially gain disease- and symptom-free time for patients,” says cooperation partner Professor Sotillo.

Also suitable for other tumors?

When macrophages took up the iron nanoparticles, they released substances that harmed the cancer cells and attracted further immune cells. After treatment with crizotinib, the tumors grew back at a significantly slower rate over the two-week trial period. There were no side effects. "These results do not yet say anything about whether and for how long lung cancer patients would benefit from such treatment. But they show a promising approach that we would also like to test in other forms of lung cancer as well as liver tumors and breast cancer,” says Muckenthaler.

Non-small cell lung cancer (NSCLC) accounts for about 80 percent of all lung tumors. The subtype of ALK-positive non-small cell lung cancer, affecting about 5 percent of NSCLC patients, is characterized by a specific genetic alteration (EML4-ALK fusion oncogene). Patients with this cancer type usually have never or rarely smoked. The usual treatment consists of treatment with targeted inhibitors such as Crizotinib. However, these tumors respond poorly to common immunotherapies.

Original publication: Superparamagnetic Iron Oxide Nanoparticles Reprogram the Tumor Microenvironment and Reduce Lung Cancer Regrowth after Crizotinib Treatment. Horvat, N.K., Chocarro, S., Marques O. et al. ACS Nano. 2024;18(17):11025-11041.

Source: DZL

Research for health and the prevention and better treatment of common diseases are the goals of the German Centers for Health Research (DZG). At the 2nd DZG Munich Day on July 12, 2024, the eight DZG in Munich will provide an overview of scientific highlights and an insight into joint research. Other focal points include the participation of patients and the presentation of poster awards.

Many people still suffer from common diseases such as diabetes, infections, cancer, cardiovascular and lung diseases as well as neurodegenerative and mental disorders. In the eight centers for the respective widespread diseases, researchers and clinicians are working successfully to bring new results from science into practice more quickly. "The German Centers for Health Research carry out cutting-edge translational research. People benefit from this through more targeted prevention and more precise treatment," emphasizes Prof. Martin Hrabě de Angelis, current spokesperson of the DZG.

Researching together and using synergies

Although the various common diseases appear to be quite different, there are often connections that are important for the development of new therapies and research methods. The active networking of the various DZGs offers a unique opportunity to develop innovative research approaches. A special focus at the 2nd DZG Munich Day will therefore be on cooperation between the centers. Current transdisciplinary projects will be presented, including on intermittent fasting, the identification of disease causes and biomarkers or research into cross-disease changes in the protein TREM2, which drives the brain's immune cells to peak performance.

Guests from politics, science and clinics

Following last year's successful start, the DZG Munich Day is being held for the second time. The event will be opened by welcoming addresses from Thomas Romes (Department of Life Sciences, Federal Ministry of Education and Research (BMBF)), Markus Blume (Bavarian State Minister of Science and the Arts), Matthias Tschöp (CEO, Helmholtz Munich), Stephanie E. Combs (Dean, TUM School of Medicine and Health) and Markus M. Lerch (Medical Director, LMU Klinikum). The work of the DZG will then be presented. The DZG's research in Munich will be presented by the site speakers.

Actively involving sick people

Patients are playing an increasingly important role in research. Their experiences and perspectives on living with a disease can provide valuable input for researchers. At the event, the DZG will present how they actively involve patients in their work (patient participation).

Poster Awards: Best posters are honored

The extensive program also includes posters presenting the latest results. This gives young talents the opportunity to present their research and talk to other researchers. The best three posters will receive awards.

The aim of the 2nd DZG Munich Day is to further expand cross-DZG exchange, strengthen existing collaborations between the various DZGs in Munich, establish new contacts and make even better use of synergies.

More informationen on 2nd DZG Munich Day 

Program of the 2nd DZG Munich Day

Source: DZD

United against common diseases! This is the mission of the German Centers for Health Research (DZGs). Their scientists are working to optimize the translation of research results into patient care, thereby significantly improving the prevention and treatment of these diseases.

It´s time: project start for the winners of this year's DZG-overarching research project in Dresden. The awardees were honored at the German Cancer Consortium (DKTK) Dresden by Prof. Mechthild Krause and Prof. Michele Solimena.

At the annual joint symposium, the three Dresden DZGs – the Paul Langerhans Institute Dresden (PLID) of the German Center for Diabetes Research (DZD), the German Center for Neurodegenerative Diseases (DZNE), and the aforementioned DKTK – once again announced seed funding for cross-DZG projects this year. The aim of this funding is to enable new translational activities between the DZGs in Dresden that arise at the thematic interfaces of the centers.

This year, one project team received €10,000 in seed funding. In the project "Metabolic-epigenetic crosstalk as a driver of aging, disease and cognitive decline", Sara Zocher (DZNE) and Zeina Nicola (DZD/PLID) want to gain new insights into the causes of brain ageing. In collaboration with Claudia Peitzsch, they are using the Mass Cytometry Facility of CRTD and use metabolic targeting to investigate the neuronal epigenome as a potential therapeutic intervention. The long-term aim is to counteract age-related brain dysfunction in this way.

Diabetes, cancer, and dementia: As different as these diseases may seem, there are often connections that are relevant for the development of therapeutic approaches and diagnostic methods. The active networking of the DZGs thus represents a unique opportunity to develop completely new and innovative research approaches. Dresden is a pioneer in this field, as the three Dresden-based DZGs have been closely connected for several years.

Diabetes, cancer and dementia: as different as these diseases may appear, there are often crosslinks that are relevant for the development of therapeutic approaches and investigative methods. The active networking of different DZGs thus reflects a unique opportunity to develop completely new and innovative research approaches. Dresden is a pioneer in this respect, as the three Dresden-based DZGs have been closely connected for several years.

Source: DZD

An innovative tool for the targeted modification of gene activity in heart muscle cells could establish itself as a standard method for research into cardiovascular diseases. Dr Patrick Laurette and his colleagues at the German Centre for Cardiovascular Research (DZHK), led by Prof. Ralf Gilsbach, have successfully reduced the activity of individual genes in mouse heart muscle cells using the CRISPRi system. This technology allows for the temporary suppression of gene expression without altering the genetic sequence. It thus avoids the potential risks associated with direct intervention in the genome.

​​CRISPRi is based on the CRISPR-Cas genome editing system but lacks the ability to cut DNA, a so-called "dead CAS" (dCAS) and is fused to a KRAB repressor domain. Using a short RNA as a molecular guide dCas9 can bind to specific DNA sequences. As a result, the target region in the genome is epigenetically silenced, and a gene can no longer be read. This blockade is called "epigenetic silencing".

To introduce the CRISPRi system into the heart muscle cells of mice, the researchers used adeno-associated viruses (AAV), which do not integrate into the genome. One challenge was to package the entire system into the limited genomic capacity of the AAVs. The researchers succeeded in doing this by using a particularly small dCAS. Although other viral vectors have more capacity in this respect, they cannot efficiently reach heart muscle cells or integrate into the genome.

Effective blockade in the heart muscle

Dr Patrick Laurette and his colleagues at Heidelberg University Hospital demonstrated how well epigenetic silencing with the AAV-CRISPRi system works in heart cells for several genes and enhancers. The activity of some genes decreased by up to 95 percent. Enhancers are regulatory elements that can fine-tune gene expression from distant genomic regions.

"The complexity of the mammalian organism is the result of around one million regulatory elements. There are between fifty and one hundred thousand of these enhancers in heart muscle cells alone," says Prof. Ralf Gilsbach. They are now focusing on modulating these regulatory elements using their new method to treat diseases such as heart failure or cardiac arrhythmia.

Translational perspective

Gilsbach emphasizes the translational significance of this approach, which makes it possible to specifically influence gene expression in vivo without changing the DNA sequence. The method is also titratable, meaning it can be regulated and its effect can be reversed. Compared to other methods, such as genetic knock-out, in which genes are destroyed, the AAV-CRISPRi system offers a more precise imitation of natural regulatory mechanisms.

Methodically optimized and further developed, the procedure could also be used for human therapy in the long term. "I am convinced that this approach has translational significance, even if it is difficult to predict how quickly development will continue here," says Gilsbach.

There are already numerous companies that are considering AAVs to deliver CRISPR components for therapies. Among other things, they are working on avoiding unwanted antibody reactions. This is because humans have antibodies against AAV and often also against the CRISPR protein derived from bacteria.

Original publication: In Vivo Silencing of Regulatory Elements Using a Single AAV-CRISPRi Vector. Laurette, P., Cao, C., Ramanujam, D. et al. Circ Res. 2024;134(2):223-225.

Source: DZHK

On June 12, 2024, a joint strategy paper "National Strategy for Gene and Cell Therapies" was presented to Federal Research Minister Bettina Stark-Watzinger. It was conceived by stakeholders from science, industry, politics, authorities, foundations, patient organizations and with the participation of the German Centres for Health Research.

In fall 2022, the Federal Ministry of Education and Research (BMBF) commissioned the Berlin Institute of Health at Charité (BIH) to coordinate the creation of a national strategy for gene- and cell-based therapies. Around 150 experts from various stakeholder groups drew up the paper and developed a roadmap for improving healthcare and strengthening Germany as a location for gene- and cell-based therapies. Several experts from the German Centers for Health Research (DZG) were also represented in the various working groups.

Gene and cell therapies (GCTs) are some of the key technologies driving innovation in biomedical research and patient care. They are not only used to modulate disease processes and alleviate symptoms, but also directly address the genetic causes of diseases. This opens promising perspectives for patients suffering from severe and rare diseases for which no treatment currently exists.

In order to improve patient access to gene and cell therapies and to strengthen Germany as an international hub for research and innovation in this field, the BMBF commissioned the BIH in fall of 2022 to coordinate and oversee the development of a National Strategy for Gene and Cell Therapies. This strategy was presented to the Federal Minister of Education and Research, Bettina Stark-Watzinger, on June 12, 2024.

“The National Strategy for Gene and Cell Therapies is an important step towards securing and expanding Germany's position as a centre of biomedical innovation. Our declared aim is to create new treatment options for patients in the long term. I am very pleased that we have succeeded in bringing together so many stakeholders from different areas and jointly developing the National Strategy. This collaboration between science, industry, the public sector and society is an important key to success. I would like to thank all those involved for their great commitment. With this spirit of optimism, we should now move forward together in a national network." says Federal Research Minister Bettina Stark-Watzinger.

Interdisciplinary measures in eight action areas

The National Strategy is chiefly characterized by its multi-stakeholder approach, which brought together a wide range of views and interests from science, business, politics, society and patient groups. Several experts from the DZG were also represented in the various working groups formed for this purpose.

The fields of action include the following topics:

I. Stakeholder networking and support
II. Training and development of skills
III. Technology transfer
IV. Standards, norms and regulatory framework
V. Improvement of quality and capacity for good manufacturing practice (GMP) production
VI. Research and development
VII. Marketing authorization and translation into patient care
VII. Interaction with society

The strategy emphasizes the tremendous potential that the cutting-edge field of gene and cell therapy has for improving patient care and the healthcare industry and for strengthening Germany as a location for pharmaceuticals and innovation. Yet measures must be taken to accelerate the translation of findings from Germany’s strong basic research programs into clinical practice, while at the same time making gene and cell therapies not only safe and efficient but also affordable and widely accessible.

What’s next for the National Strategy for Gene and Cell Therapies?

The proposed measures will now be implemented step by step in collaboration with all stakeholders. A number of other activities have already been initiated alongside the drafting of the strategy. These include the creation of a National Network Office for Gene and Cell Therapies, the establishment of the nationwide entrepreneurship program GeneNovate, the offering of low-threshold advice on regulatory issues and the laying of the groundwork for funding to support researchers and projects in the field of gene and cell therapy. The Network Office is tasked with building a national GCT community that brings together all stakeholder groups through independent, cross-site information exchange and networking. A total of 48 million euros is available for the design and implementation of the strategy's measures in the period 2023-2026.

Download: National Strategy for Gene and Cell therapies

Source: BIH press release

What happens in the body when we are hungry and see and smell food? A team of researchers at the DZD and the Max Planck Institute for Metabolism Research has now been able to show in mice that adaptations in the liver mitochondria take place after only a few minutes. Stimulated by the activation of a group of nerve cells in the brain, the mitochondria of the liver cells change and prepare the liver for the adaptation of the sugar metabolism. The findings, published in the journal Science, could open up new avenues for the treatment of type 2 diabetes.

The researchers fed hungry mice that could only see and smell the food without eating it. After just a few minutes, the researchers analysed the mitochondria in the liver and found that processes normally stimulated by food intake were activated.

Mitochondria in the liver get ready

The studies show that it is sufficient for the mice to see and smell food for a few minutes to influence the mitochondria in the liver cells. This is mediated by a previously uncharacterised phosphorylation in a mitochondrial protein. Phosphorylation is an important modification for the regulation of protein activity. The researchers also show that this phosphorylation affects the sensitivity of the liver to insulin. The researchers have thus discovered a new signalling pathway that regulates insulin sensitivity in the body.

Nerve cells in the hypothalamus

The effect on the liver is mediated by a group of nerve cells called POMC neurons. These neurons are activated within seconds by the sight and smell of food, signalling the liver to prepare for the incoming nutrients. The researchers also showed that the activation of POMC neurons alone is sufficient to adapt the mitochondria in the liver, even in the absence of food.

"When our senses detect food, our body prepares for food intake by producing saliva and digestive acid. We knew from previous studies that the liver also prepares for food intake. Now we have taken a closer look at the mitochondria in liver cells, because they are essential cell organelles for metabolism and energy production, and realised how surprisingly fast this adaptation takes place," explains Sinika Henschke, first author of the study.

Jens Brüning, head of the study and director at the Max Planck Institute for Metabolism Research: "Our study shows how closely the sensory perception of food, adaptive processes in the mitochondria and insulin sensitivity are linked. Understanding these mechanisms is also important because insulin sensitivity is impaired in type 2 diabetes mellitus".

Jens Brüning is also a research group leader at the CECAD Cluster of Excellence in Ageing Research at the University of Cologne and Director of the Department of Endocrinology, Diabetology and Preventive Medicine at Cologne University Hospital as well as associated partner in the German Center for Diabetes Research (DZD).

Originalpublikation: Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver. Henschke, S., Nolte, H., Magoley, J. et al. Science 2024; 384: 438-446.

Quelle: DZD

 

Dedicated memory tests on smartphones enable the detection of “mild cognitive impairment”, a condition that may indicate Alzheimer’s disease, with high accuracy. Researchers from DZNE, the Otto-von-Guericke University Magdeburg and the University of Wisconsin-Madison in the United States who collaborated with the Magdeburg-based company neotiv report these findings in the scientific journal npj Digital Medicine. Their study is based on data from 199 older adults. The results underline the potential of mobile apps for Alzheimer’s disease research, clinical trials and routine medical care. The app that has been evaluated is now being offered to medical doctors to support the early detection of memory problems.

Memory problems are a key symptom of Alzheimer’s disease. Not surprisingly, their severity and progression play a central role in the diagnosis of Alzheimer’s disease and also in Alzheimer’s research. In current clinical practice, memory assessment is performed under the guidance of a medical professional. The individuals being tested have to complete standardized tasks in writing or in conversation: for example, remembering and repeating words, spontaneously naming as many terms as possible on a certain topic or drawing geometric figures according to instructions. All these tests necessarily require professional supervision, otherwise the results are not conclusive. Thus, these tests cannot be completed alone, for example at home.

Prof. Emrah Düzel, a senior neuroscientist at DZNE’s Magdeburg site and at University Magdeburg as well as entrepreneur in medical technology, advocates a new approach: “It has advantages if you can carry out such tests on your own and only have to visit the doctor’s office to evaluate the results. Just as we know it from a long-term ECG, for example. Unsupervised testing would help to detect clinically relevant memory impairment at an earlier stage and track disease progression more closely than is currently possible. In view of recent developments in Alzheimer’s therapy and new treatment options, early diagnosis is becoming increasingly important.”

Comparison between remote at-home and supervised in-clinic testing

In addition to his involvement in dementia research, Düzel is also “Chief Medical Officer” of “neotiv”, a Magdeburg-based start-up with which the DZNE has been cooperating for several years. The company has developed an app with which memory tests can be carried out autonomously with no need for professional supervision. The software runs on smartphones and tablets, and has been scientifically validated; it is used in Alzheimer’s disease research and is now also offered as a digital tool for medical doctors to support the detection of mild cognitive impairment (MCI). Although MCI has little impact on the affected individuals daily living, they have nevertheless an increased risk of developing Alzheimer’s dementia within a few years.

Dr. David Berron, research group leader at DZNE and also co-founder of neotiv explains: “As part of the validation process, we applied these novel remote and unsupervised assessments as well as an established in-clinic neuropsychological test battery. We found that the novel method is comparable to in-clinic assessments and detects mild cognitive impairment, also known as MCI, with high accuracy. This technology has enormous potential to provide clinicians with information that they cannot obtain during a patient vist to the clinic.” These findings have now been published in the renowned scientific journal “npj Digital Medicine”.

Participants from Germany and the USA

A total of 199 women and men over the age of 60 participated in the current study. They were located either in Germany or the USA and were each involved in one of two long-term observational studies, both of which address Alzheimer’s – the most common dementia: DZNE’s DELCODE study (Longitudinal Cognitive Impairment and Dementia Study) and the WRAP (Wisconsin Registry for Alzheimer's Prevention) study of the University of Wisconsin-Madison. The study sample reflected varying cognitive conditions as they occur in a real world situation: It included individuals who were cognitively healthy, patients with MCI and others with subjectively perceived but not measurable memory problems. The diagnosis was based on established assessments that included e. g. memory and language tasks. In addition, all participants completed multiple memory assessments with the neotiv app over a period of at least six weeks, using their own smartphones or tablets – and wherever it was convenient for them. “We found that a majority of our WRAP participants were able to complete the unsupervised digital tasks remotely and they were satisfied with the tasks and the digital platform,” says Lindsay Clark, PhD, neuropsychologist and lead investigator of the Assessing Memory with Mobile Devices study at the University of Wisconsin-Madison.

Remembering images and detecting differences

“Assessments with the neotiv app are interactive and comprise three types of memory tasks. These address different areas of the brain that can be affected by Alzheimer’s disease in different disease stages. Many years of research have gone into this,” Düzel explains. Essentially, these tests involve remembering images or recognizing differences between images that are presented by the app. Using a specially developed score, the German-US research team was able to compare the results of the app with the findings of the established in-clinic assessments. “Our study shows that memory complaints can be meaningfully assessed using this digital, remote and unsupervised approach,” says Düzel. “If the results from the digital assessment indicate that there is memory impairment typical of MCI, this paves the way for further clinical examinations. If test results indicate that memory is within the age-specific normal range, individuals can be given an all-clear signal for the time being. And for Alzheimer’s disease research, this approach provides a digital cognitive assessment tool that can be used in clinical studies – as is already being done in Germany, the USA, Sweden and other countries.”

Outlook

Further studies are in preparation or already underway. The novel memory assessment is to be tested on even larger study groups, and the researchers also intend to investigate whether it can be used to track the progression of Alzheimer’s disease over a longer period of time. Berron: “Information about how quickly memory declines over time is important for medical doctors and patients. It is also important for clinical trials as new treatments aim to slow the rate of cognitive decline.” The cognitive neuroscientist describes the challenges: “To advance such self-tests, a patient’s clinical data must be linked to self-tests outside the clinic, in the real-world. This is no easy task, but as our current study shows, we are making progress as a field.”

Original publication: A Remote Digital Memory Composite to Detect Cognitive Impairment in Memory Clinic Samples in Unsupervised Settings using Mobile Devices. Berron, D., Glanz, W., Clark, L. et al. npj Digit. Med. 2024 7, 79.

Source: DZNE

Social isolation and loneliness are major social problems. Their negative impact on mental health has been exacerbated worldwide by the Covid-19 pandemic. Researchers at the Central Institute of Mental Health (CIMH) in Mannheim, in collaboration with scientists from the Karlsruhe Institute of Technology (KIT), the Ruhr University Bochum (RUB), and the University of Bern, have investigated the extent to which physical activity can mitigate the negative effects of social isolation on well-being. The interdisciplinary research team, including scientists from the DZPG, has published the results of its study in the journal Nature Mental Health.

Positive effects of exercise

The study shows that people who were currently alone in their daily lives reported a comparatively lower level of well-being, but this increased when they were physically active. The data suggest that physical activity, such as walking for one hour at a speed of five kilometers per hour, can compensate for the current "social-affective deficit". In further exploratory analyses, the researchers describe that this beneficial effect of exercise persisted even at lower levels of physical activity and during pandemic-related restrictions. Investigations of the subjects' brain function also showed that people at increased neural risk for depression and loneliness benefited particularly from a more physically active lifestyle.

The study included 317 young adults and a second group of 30 adults who were examined during the Covid-19 pandemic. The researchers used a variety of methods for their study, including accelerometers, smartphones with electronic diaries, and brain imaging. This approach allowed the researchers to study the complex interplay between social contact, physical activity, and psychological well-being in everyday life, and to identify the associated brain functions.

Dynamic interplay

"Previous studies have mostly examined social contact and physical activity independently. Our study extends this knowledge by showing a dynamic interplay between these two factors in everyday life, which has an impact on affective well-being," says Anastasia Benedyk from the Department of Psychiatry and Psychotherapy at the ZI, who is the first author of the study together with Prof. Dr. Markus Reichert (CIMH and RUB).

Prof. Dr. Dr. Heike Tost, also from the Department of Psychiatry and Psychotherapy at the CIMH, adds: "The results suggest that physical activity can be used as an effective and accessible strategy to counteract the psychological effects of loneliness and improve public health".

Original publication: Real-life behavioral and neural circuit markers of physical activity as a compensatory mechanism for social isolation. Benedyk, A., Reichert, M., Giurgiu, M. et al. Nat Mental Health 2.2024:337–342.

Source: DZPG

The German Center for Paediatric and Adolescent Medicine (DZKJ) will become a new partner of the German Centers for Health Research (DZG) from June 1, 2024. This expands the number of DZG centers to eight. The aim of the German Centers for Health Research is to combat particularly common diseases - the widespread diseases - more effectively. The DZG were established on the initiative of the Federal Ministry of Education and Research (BMBF).

The nationally organized and networked research center will receive 30 million euros in funding from the Federal Ministry of Education and Research during the two-year start-up phase. The DZKJ office will be located at the University Medical Center Göttingen (UMG). The aim of the Göttingen partner site is to develop personalized medicine specifically for children and adolescents with neurological and developmental diseases.

Childhood and adolescence are key developmental phases in which the fundamental course for lifelong health is set. Another German Center for Health Research has been established to ensure the best possible disease detection and treatment as well as comprehensive care according to the latest state of research during this time.

Seven partner sites: Berlin, Göttingen, Greifswald/Rostock, Hamburg, Leipzig/Dresden, Munich and Ulm

The future German Center for Paediatric and Adolescent Medicine (DZKJ) pools the specialist expertise of university hospitals and universities at seven partner locations: Berlin, Göttingen, Greifswald/Rostock, Hamburg, Leipzig/Dresden, Munich and Ulm. Experts from various fields of research work together here on a cross-thematic basis.

In addition to university hospitals and universities, non-university research institutions such as Max Planck Institutes, Fraunhofer Institutes, Helmholtz and Leibniz Centers are also involved. After the start-up phase, long-term institutional funding is to follow.

Prof. Dr. Jutta Gärtner, Göttingen, spokesperson for the DZKJ and Director of the Department of Paediatric and Adolescent Medicine at the University Medical Center Göttingen (UMG), explains the mission of the new center: “Paediatric and adolescent medicine encompasses the entire complex spectrum of diseases of the developing organism. Cross-organ disease mechanisms and treatment approaches play a central role in this. Thanks to the close collaboration between the experts at the DZKJ, the latest research findings will benefit young patients directly and promptly."

Cross-site platforms and DZKJ Academy

The interdisciplinary research covers a broad spectrum from rare genetic diseases, immunity, inflammation, infection, development of the central nervous system and neurological diseases, obesity, early determinants of health and disease, psychosocial and mental health to community medicine.

Platforms for clinical studies, research data management and new biotechnological methods, for example omics technologies, gene and cell therapies, will be established across all locations. A joint platform will promote cooperation with the German Center for Mental Health (DZPG), which is also being established.

The establishment of a DZKJ-wide patient and test subject cohort and the preparation of joint clinical studies and biobanks are important cross-sectional activities. The promotion of young scientists is of particular importance. Special training and mentoring programs will be developed as part of an overarching DZKJ Academy.

Affected people get involved in research

Children and adolescents as well as their parents are involved in research activities and the organization of the center from the very beginning. A particular focus is on empowering patients to become directly involved in the planning and implementation of research projects. Parent representative Anja Bratke and patient representative Stephan Kruip say: “We see an opportunity for both the research projects and the children and their parents to benefit from this new type of patient involvement. Children and adolescents are often already little experts when it comes to their own illness. Involving them and their parents in the newly founded DZKJ in such an innovative way is a major step towards strengthening patients' rights."

The DZKJ will make an important contribution to international cutting-edge research in the field of pediatric and adolescent medicine through interdisciplinary and innovative research. The aim is to ensure that children and adolescents in Germany receive optimal, state-of-the-art disease detection and treatment at all stages of their development.

Source: Joint press release of the University Medical Center Göttingen (UMG) and the German Center for Paediatric and Adolescent Medicine (DZKJ)

Patients have regular check-ups during and after lung cancer treatment to see whether the treatment is successful in the long term - or whether the cancer has returned. This is extremely important for both the treating physicians as well as the patients. A DZL research team has now discovered that the presence of the protein glycodelin in the blood indicates that a therapy is failing. This leads to some interesting conclusions.

Immunotherapies reactivate the body's own defences to fight a tumor. For non-small cell lung cancer (NSCLC), the survival times of patients treated in this way improved significantly. However, immunotherapy does not work for everyone. This suggests that additional mechanisms are involved.

Early results from Heidelberg

In earlier studies, scientists from the DZL site TLRC Heidelberg had already established that lung tumors produce the mRNA for glycodelin. Women with such tumors have a reduced survival rate. The physiological function of the glycodelin protein is to downregulate the maternal immune system of the uterus at the beginning of pregnancy. This is necessary to prevent it from recognizing the fetus as ‘foreign’. Tumors take advantage of this function by upregulating the production of glycodelin.

New findings on the mode of action of glycodelin

The aim of the new study was to investigate the underlying mechanisms of action of glycodelin in more detail. To this end, the Heidelberg researchers teamed up with scientists from the Borstel Research Center at the DZL site ARCN. Together, they were able to show that glycodelin binds strongly to certain subgroups of immune cells and thus influences various signaling pathways. Genes associated with inflammatory processes or the tumor environment were deregulated. Multiplex immunofluorescence staining, which allows the parallel detection and spatial localization of a large number of surface proteins, revealed that these immune cells include CD8-positive T lymphocytes. It is precisely these T cells - also known as "cytotoxic" - that play an important role in immunotherapies. It is conceivable that glycodelin blocks their effect and thus contributes to treatment failure.

Clinical potential

Further studies have now shown that glycodelin can also be found in the blood of both male and female patients. There was a clear link between high levels and early tumor recurrence - but only in women. Glycodelin therefore contributes to the suppression of the immune system and thus to the recurrence of the tumor.

This marks out Glycodelin as an important sex-specific marker that could be used in therapy monitoring. It is also conceivable to develop an antibody that blocks glycodelin. In this way, the tumor could be deprived of one of the options of evading therapy. Dr. Sebastian Marwitz from the Research Center Borstel is optimistic: "The results on the sex-specific role of glycodelin offers an excellent first step towards precision medicine and targeted treatment for female patients."

Successful cooperation within the DZL

These new insights gained were achieved through a collaboration between scientists from the German Cancer Research Center, the Thoraxklinik and the University of Heidelberg (all three belong to DZL site TLRC) and the Research Center Borstel (DZL site ARCN). It was published earlier this month in the journal Translational Research. The publication’s first author, Sarah Richtmann, was supported by the Mobility Grant Program of the DZL Academy.

Original publication: The pregnancy-associated protein glycodelin as a potential sex-specific target for resistance to immunotherapy in non-small cell lung cancer. Richtmann, S., Marwitz, S., Muley, T. et al. Transl Res. 2024 Mar 13;(24):1931-5244.

Source: DZL

Over 12 million people worldwide suffer from a chronic infection with the hepatitis D virus. This most severe viral liver disease is associated with a high risk of dying from liver cirrhosis and liver cancer. It is caused by the hepatitis D virus (HDV), which uses the surface proteins of the hepatitis B virus (HBV) as a vehicle to specifically enter liver cells via a protein in the cell membrane—the bile salt transporter protein NTCP. This cell entry can be prevented by the active agent bulevirtide, which is approved as a drug under the name Hepcludex.

An international research team has now succeeded in deciphering the molecular structure of bulevirtide in complex with the HBV/HDV receptor NTCP at the molecular level. The research results published in the renowned journal Nature Communications pave the way for more targeted and effective treatments for millions of people chronically infected with HBV/HDV.

The entry inhibitor bulevirtide is the first and currently only approved drug (under the drug name Hepcludex) for the treatment of chronic infections with the hepatitis D virus. The active agent effectively inhibits the replication of hepatitis D viruses and leads to a significant improvement in liver function. However, the exact mechanism by which bulevirtide interacts with the virus entry receptor on the surface of the liver cells—the bile salt transporter protein NTCP (short for: sodium taurocholate cotransporting polypeptide)—and thereby inhibits the entry of the viruses into the cells was previously unknown.

In order to understand the molecular interaction of bulevirtide and NTCP at the molecular level, the researchers first generated an antibody fragment that specifically recognises the NTCP-bulevirtide complex and makes it accessible for analysis when bound to nanoparticles. This complex was then analysed using cryo-electron microscopy, which allowed to visualise structural details with atomic resolution. The research results represent a milestone in understanding both the interaction of HBV and HDV with their cellular entry receptor NTCP and the mechanism of cell receptor blockade by bulevirtide.

How bulevirtide blocks the cell entry receptor NTCP

The analysis showed that bulevirtide forms three functional domains in the interaction with the HBV/HDV receptor NTCP: a myristoyl group that interacts with the cell membrane on the outside of the cell; an essential core sequence ('plug') that fits precisely into the bile salt transport tunnel of the NTCP like the bit of a key into a lock; and an amino acid chain that stretches across the extracellular surface of the receptor, enclosing it like a brace. 

"The formation of a 'plug' in the transport tunnel and the associated inactivation of the bile salt transporter is so far unique among all known virus-receptor complexes. This structure explains why the physiological function of the NTCP is inhibited when patients are treated with bulevirtide," says Prof Stephan Urban, DZIF Professor of Translational Virology and Deputy Coordinator of the DZIF research area Hepatitis, in whose laboratory at Heidelberg University the active agent bulevirtide was developed. 

"Thanks to the structural details of the interaction with bulevirtide, we have also gained insights that enable the development of smaller active agents—so-called peptidomimetics—with improved pharmacological properties. Our structural analysis also lays the foundation for the development of drugs that are not only based on peptides and possibly enable oral administration," adds the co-author of the study, Prof Joachim Geyer from the Institute of Pharmacology and Toxicology at Justus Liebig University Giessen. 

Evolutionary adaptation of hepatitis B viruses to host species

The structural analysis also helped to decode an important factor in the species specificity of hepatitis B and D viruses. According to the findings of the analysis, the amino acid at position 158 of the NTCP amino acid chain plays an essential role in virus-receptor interaction. A change in the amino acid at this position prevents the binding of HBV/HDV. This explains why certain Old World monkeys, such as macaques, cannot be infected by HBV/HDV. 

"Our findings enable a deeper understanding of the evolutionary adaptation of human and animal hepatitis B viruses to their hosts and also provide an important molecular basis for the development of new and targeted drugs," adds co-author Prof Dieter Glebe, DZIF scientist at the Institute of Medical Virology at Justus Liebig University Giessen. 

"Our research results are an important step in the fight against hepatitis D and B. By understanding the structure of bulevirtide and its binding to NTCP, we can potentially develop more targeted and effective treatments for millions of people chronically infected with HBV/HDV," says Prof. Kaspar Locher, last author of the publication and head of the internationally renowned structural biology team at ETH Zurich, summarising the study results.

Original publication: Structure of antiviral drug bulevirtide bound to hepatitis B and D virus receptor protein NTCP. Liu, H., Zakrzewicz, D., Nosol, K. et al. Nat Commun. 2024 Mar 20;15(1):2476.

Source: DZIF