NCRC-Brain4Lab-Projekte (2022-2023)

PSE@NCRC and cRDM@NCRC: Keeping NeuroCure at the forefront of responsible translational neuroscience

NeuroCure PI: Ulrich Dirnagl
NeuroCure Co-PIs: Isabel Dziobek, Matthias Endres
Collaboration partners: Stefanie Märschenz, René Bernard, Evgeny Bobrov, Sarah Weschke, Petra Ritter

In cooperation with the QUEST Center of the BIH this project will add two novel structural elements, patient & stakeholder engagement (PSE) and clinical research data management (cRDM), to the NeuroCure cluster that will – together with the newly established Value and Open Science (VOS) module – support researchers in their translational research activities. Together they bring the clinical arm of the cluster closer to its ambitious promise to develop novel therapies and diagnostic measures benefiting patients. At the same time, they will align clinical NeuroCure research with increased expectations of funders, patients, and society towards responsible translational neuroscience. You will find more information here.
BrainBank

NeuroCure PI: Frank Heppner
NeuroCure Co-PI: Nikolaus Rajewsky
Collaboration partners: Matthias Endres, Ana Pombo, Carmen Birchmeier, Michael Brecht

By maintaining and extending the BrainBank Nucleus providing the entire general logistics including active recruitment and autopsies of patients preferentially with neurodegenerative diseases, we would like to (i) ensure sustainability of the BrainBank and (ii) extend inclusion of patients with other neurological diseases beyond neurodegeneration, to facilitate and accelerate translation within NeuroCure. Thus, besides continuing our basic BrainBank Nucleus work, we aim to provide tissue/body fluids for a collection of small pilot studies and/or follow-up projects. The focus will be on the following projects:

Spatial mapping of different neurodegenerative disease drivers (Rajewsky), A somatosensory cortical model of the human lips (Brecht), Pilot study cohort with stroke patients (Endres), Genome Architecture Mapping of fresh human brain in neurodegenerative diseases (Pombo), Vagal sensory neurons regulating for vocalization, respiratory and digestive functions (Birchmeier).
Human tissue: comprehensive approaches to study pathophysiological mechanisms of neuro-psychiatric disorders

NeuroCure PI: Dietmar Schmitz
NeuroCure Co-PIs: Frank Heppner, Benjamin Judkewitz, Matthew Larkum, Andrew Plested, Nikolaus Rajewsky, Christian Rosenmund
Collaboration partners: Pawel Fidzinski, Jörg Geiger, Martin Holtkamp, Angela Kaindl, Arend Koch, Marina Mikhaylova, Julia Onken, Harald Prüß, Helena Radbruch, Ulrich-Wilhelm Thomale, Peter Vajkoczy, Imre Vida

The main goal of the platform is the interdisciplinary investigation of physiological and pathophysiological mechanisms in neuropsychiatric disorders. Direct investigation of human brain tissue carries the potential to reduce the translational gap in neurology and psychiatry. So far, we established the platform and increased tissue availability to enable multimethodological assessments, discovering unknown mechanisms of neuronal function. We are now extending the platform for cross-validation of established and investigation of diagnostic and therapeutic approaches for patients. To place novel diagnostic and therapeutic approaches in the proper physiological context and relate these to disease-associated conditions, we focus on the characterization of translationally relevant aspects of human neuronal function, e.g. cellular variety, connectivity of local circuits, modes of synaptic transmission or rules of homeostatic plasticity.
Towards multimodal DBS-programming

NeuroCure PI: Andrea Kühn
NeuroCure Co-PIs: Matthias Endres
Collaboration partners: Julian Neumann, Petra Ritter, Christian Meisel, Katharina Faust

Deep Brain Stimulation (DBS) targeted at the subthalamic nucleus is highly efficacious in improving motor symptoms in advanced Parkinson’s Disease. Treatment success, however, depends on the correct programming of the device, which includes adaptation of stimulation frequency, pulse-width, amplitude, and the distribution of electric current across up to eight contacts at the tip of the electrode. Currently, the subject-specific optimization of these parameters follows a trial-and-error process in which highly trained medical personnel adapts the stimulation settings according to clinical effects of each setting. However, this trial-and-error process is compounded by multiple factors including a delayed response to novel stimulation settings, symptom fluctuations and patient fatigue. Hence, only a fraction of the vast amount of parameter combinations can be properly tested.Data-driven algorithms to guide programming by pre-suggesting a subset of stimulation parameters have been proposed. A promising input parameter for such algorithms is electrode location, which can be reconstructed using neuroimaging data. An algorithm for image-guided DBS was developed in our lab and its effectiveness is currently being investigated within a clinical trial funded by the NCRC Brainlab.
Another promising way to guide programming is through electrophysiological signals recorded at the stimulation site itself. Novel DBS systems that were approved for the European market in April 2021, combining sensing technologies with state-of-the-art directional electrode design, now facilitate the use of local field potentials as biomarker for DBS programming.
In this study, we are aiming to combine biomarkers of both modalities to boost accuracies of outcome predictions. We are hoping that this multimodal approach will pave the way for guided DBS programming to play a central role in postoperative patient management.
Investigate the effects of spermidine supplementation on the immune system and inflammatory parameters in old and young adults (Immuneage)

Neurocure PI: Stephan Sigrist
Neurocure Co-PI: Dietmar Schmitz, Volker Hauke, Matthias Endres
Collaboration partners: Tilman Grune, Kristina Norman, Agnes Flöel

ImmuneAge investigates the effects of polyamine-rich food supplements for strengthening the immune system of young adults and old adults, who are affected by immunosenescence.
This pilot study aims to identify biological parameters of the immune system that change following 20 days of 'high dose' spermidine treatment. Based on the results of this clinical trial supported by laboratory mechanistic molecular research, a follow-up clinical Phase 1 will be conducted exploring the efficacy of the immune system response to vaccinations upon spermidine supplementation.
The principal purpose of ImmuneAge is to introduce spermidine supplementation as a strategy for strengthening the immune system and thereby maximizing vaccine efficacy in the elderly and/ or people with otherwise compromised immune system.
In light of the currently increasing need to combat viral infections, we are highly motivated to research novel strategies for a better immune response to vaccinations. With vast literature on its benefits, especially on reversing immunosenescence, polyamine spermidine seems to be a highly potent agent in this venue.
Assessing the role of microglia activation in the pathogenesis NMDA-receptor mediated autoimmune encephalitis

NeuroCure PI: Craig Garner
NeuroCure Co-PIs: Ulrich Dirnagl, Matthias Endres, Frank Heppner, Dietmar Schmitz
Collaboration partners: Harald Prüß, Pawel Fidzinski, Jörg Geiger, Friedemann Paul, Tengis Gloveli, Christian Madry

In a number of neurodegenerative disorders, auto-antibodies have been detected suggesting that the immune system may contribute to disease progression. To test this hypothesis, we will examine whether the local delivery of human autoantibodies against neuronal proteins Lgl1, NMDAR or GABAA receptor leads not only to the activation of microglia and other immune cells, but also the stripping of these molecules from expressing cells. We also plan to explore whether these antibodies also exacerbate synaptic and neuronal loss in mouse models of AD, through the over activation of microglia, a condition that would contribute to dementia.
The Brain4Lab Data Management and Analysis Platform for Improved Diagnosis, Therapy and Prognostication in Monitored Care Units of Neurology and Psychiatry (Brain4Lab DM&AP)

NeuroCure PI: Matthias Endres
NeuroCure Co-PI: Ulrich Dirnagl, Andrea Kühn, Andreas Heinz
Collaboration partners: Franziska Scheibe, Andreas Meisel, Christian Meisel, Stefanie Märschenz, Jens-Michael Krämer, Fabian Prasser, Christof von Kalle, Daniel Strech, Felix Balzer, Jan Scheitz, Christian Nolte, Petra Ritter, Harald Prüß, Julian Neumann, Stefan Wolf, Jens Dreier, Christoph Leithner, Chotima Böttcher, Ludwig Schlemm

BrainLab DM&AP is a highly specialized research infrastructure at the interface between the M102i NeuroIntensive Care Unit (NICU), the Stroke Units (SU), NeuroCure and BIH that aims to improve diagnosis, therapy and prognostication of outcome and response to treatment in Neurocritical Care & Stroke Unit patients. The key structural element is the Data Warehouse Connect system, which connects to BIH's Health Data Platform (HDP) and enables the recording, storage, and analysis of multimodal patient (neuro) monitoring data in conjunction with the analysis of sophisticated neuroimaging, electrophysiological, and laboratory results using artificial intelligence, specifically machine learning and deep learning algorithms. The ultimate goal is to develop a clinical decision support system to assist healthcare providers in the NICU and SU setting.
Does Early-Life Stress Promote Protracted Neuroinflammation in Humans? Towards Understanding of Early Developmental Origins of Accelerated Brain Ageing (StressBrainAge)

NeuroCure PI: Christine Heim
NeuroCure Co-PI: Matthias Endres
Collaboration partners: Claudia Buss, Sonja Entringer

This project addresses the profound and lifelong programming effects of exposure to an adverse early environment on later-life increased risk for accelerated brain ageing, cognitive decline, and neurodegenerative disorders. Using non-invasive multimodal neuroimaging (f/MRI, particularly MR spectroscopy and Multi-Parameter-Mapping), we will elucidate whether early-life stress (ELS), such as abuse, neglect, or parental loss, is associated with neuroinflammation and accelerated brain ageing by computationally predicting a “brain age score”. We will then link these markers to cognitive decline and ageing-related neurological disease and determine whether markers of peripheral inflammation including but not limited to telomere length, pro-/anti-inflammatory cytokines, plasma amyloid concentrations and immunosenescence reflect neuroinflammation and subsequent brain ageing after ELS exposure. The currently funded study will extend the sample to include adult males to allow for assessment of sex differences in observed effects. This project will generate novel and unprecedented insights into the developmental origins of neuroinflammation, brain ageing and age-related brain disorders in humans. This will allow us to identify early onset trajectories of ageing-related disease after ELS. Lastly, we aim to identify targets for intervention such as anti-inflammatories or therapies.
A systematic multilevel comparison between physiological signatures of exogenous and endogenous psychoses (Repose)

NeuroCure PI: Andreas Heinz
NeuroCure Co-PI: Matthias Endres
Collaboration partners: Felix Bermpohl, Benjamin Blankertz, Eva Brandl, Stephan Brandt, Jakob Kaminski, Susanne Koch, Stephan Köhler, Tim Neumann, Josef Priller, Harald Prüß, Michael Rapp, Daniel Senkowski, Surjo R. Soekadar, Claudia Spies, Sascha Treskatsch

Following a dimensional approach, we will systematically assess the psychopathological, immunological and neurophysiological correlates of non.affective and affective psychotic disorders, including delirium and the schizophrenia spectrum. We will compare frequency of visual versus acoustic hallucinations, self-disorders and clouding of consciousness. Additionally, we will assess electroencephalography and biomarkers indicating autoimmune processes among patients with schizophrenia and schizoaffective disorders, psychotic depression and mania, delirium and acute organic hallucinations and delusions. We will assess symptom development over time with ecological momentary assessment relying on patient-reported outcome measures.
Sildenafil for the treatment of maternally inherited Leigh syndrome (MILS) (cureMILS)

NeuroCure PI: Markus Schülke-Gerstenfeld
NeuroCure Co-PI: Ulrich Dirnagl
Collaboration partners: Harald Stachelscheid, Stefanie Märschenz, Fabian Schumacher, Theresa Keller

Leigh syndrome (LS) is a severe neurodevelopmental disorder being caused by genetic defects of the nuclear or mitochondrial DNA. Basal ganglia and brainstem necroses, and muscle weakness are frequent symptoms. The most frequently affected gene is the mtDNA-encoded MT-ATP6 gene that encodes part of the mitochondrial ATP-producing machinery. This condition is inherited through the maternal mtDNA lineage and is therefore called “maternally inherited LS” (MILS). Currently, there is no therapy and patients show progressive neurodegeneration after each metabolic crisis, leading to multisystem disability and early death. Recently, we found sildenafil (Viagra®, Revatio®) to have a beneficial effect on neuronal cells derived from MILS patients. With this study, we want to prepare a multicenter trial on the treatment of MILS with sildenafil. We will seek patient/parent/stakeholder involvement into the clinical trial design, establish pharmacovigilance, and perform additional calcium imaging assays to investigate the mechanism of action of sildenafil in MILS iPSC-derived neurons.
Towards precision medicine in autism spectrum disorder (ASD): Neurobiological mechanisms and predictors of cognitive behavioral therapy in adults with high-functioning ASD (Neuroscience-informed CBT in ASD)

NeuroCure PI: Isabel Dziobek
Collaboration partners: Ludger Tebartz van Elst, Stephan Ripke

Project description will follow soon.