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Exploring modulators of tau spreading in Alzheimer’s disease through multi-modal neuroimaging biomarkers
Get PDFAlzheimer’s disease (AD), the leading cause of dementia worldwide, is characterised by a cascade of pathological brain changes starting with the emergence of amyloid plaques decades before the eventual spreading of tau pathology which drives the development of dementia symptoms. There is significant heterogeneity within AD, leading to variations in how the condition manifests clinically and the trajectory in which it progresses. This clinical heterogeneity can be related to heterogeneity in the pathophysiological underpinnings of AD, specifically pertaining to tau pathology which has been identified as the main driver of neurodegeneration, giving rise to distinct clinical phenotypes depending on the deposition pattern and accumulation rate of tau pathology. Specifically, neuroimaging studies demonstrate individual variations in the spreading rate and spatial pattern of tau pathology which correspond to clinical manifestation and progression. However, our understanding of the mechanisms responsible for these variations in tau pathology progression in AD remains limited. Given that tau plays a pivotal role in neurodegeneration and cognitive decline, understanding its modulators is paramount for optimising therapeutic interventions against AD progression. The aim of this thesis was to uncover factors impacting tau spreading through multimodal neuroimaging and genetic markers, with the primary objective of advancing our comprehension of AD pathophysiological progression, and ultimately aiding the development of more precise therapeutic strategies against AD.
Recent translational research combining resting-state functional magnetic resonance imaging (rs-fMRI) and tau-positron emission tomography (PET) reveals that tau spreading is activity dependent. Originating from focal areas typically within the medial temporal lobe, tau progressively expands out across the cortex, traversing functionally connected brain regions. This observation demonstrates how tau progression takes distinct routes depending on brain network architecture. Building on this evidence, the first investigation of this dissertation tested whether the functional organisation of the brain i.e., the functional connectome, impacted the rate at which tau accumulation progresses through the cortex. Considering that the functional connectome is of a modular structure made up of communicative but distinct networks, longitudinal exploration was conducted to ascertain whether the baseline rs-fMRI defined functional segregation of networks was associated with the rate of annual tau-PET SUVR change. In a sample of 123 subjects either cognitively healthy or spanning the AD spectrum, it was demonstrated that higher network segregation is associated with an attenuated rate of tau spreading. Moreover, we further demonstrated that the functional segregation of subject-specific tau epicentres i.e., the region where tau initially manifests, influences the subsequent trajectory of tau spreading whereby more segregated epicentres lead to lower tau accumulation rates in the most connected regions and slower future tau progression overall. Together, these results indicate that the spread of tau pathology is influenced by the brain’s functional organisation. Specifically, a more diffuse brain network architecture facilitates inter-regional tau spreading, signifying that individual variations in tau-trajectories may be shaped by the brain’s functional architecture.
In the light of new anti-amyloid therapies, the second investigation was conducted into modulators of tau progression in relation to amyloid. Given that amyloid initiates AD’s pathological cascade, triggering tau propagation, it is crucial to identify factors that moderate this. This is essential for optimising therapeutic windows for anti-amyloid treatments to intercept tau before it drives clinical disease progression. The Apolipoprotein E 4 (ApoE4) allele is the strongest known genetic risk-factor for sporadic AD, whereby carriers have increased amyloidosis and faster AD progression, however, how ApoE4 influences amyloid-related tau spreading is unclear. Therefore, we explored connectivity mapped individualised tau spreading trajectories corresponding to amyloid levels using PET data from 367 ApoE genotyped subjects spanning two independent samples to determine the influence of ApoE4 carriage on amyloid’s potential to trigger tau spreading. Results demonstrated that ApoE4 carriers had increased tau accumulation mediated by stronger amyloid deposition in early spreading stages and an accelerated tau spreading trajectory starting at lower amyloid levels. These findings indicate an indirect effect of ApoE4 carriage on tau spreading by driving increased amyloidosis, but also a direct effect whereby tau spreading was triggered earlier and faster relative to amyloid levels in ApoE4 carriers. This implies a need to intervene with anti-amyloid therapies in ApoE4 carriers earlier, to intercept tau progression promptly.
In summary, this thesis introduces novel evidence concerning modulators of tau progression in vivo, by employing a multi-modal neuroimaging approach to reflect the connectivity mediated spreading of tau pathology throughout the AD spectrum. Utilising longitudinal tau-PET, individualised patterns of tau spreading were tracked and mapped to brain connectivity dynamics derived from rs-fMRI data, revealing that the onset and pace of tau spreading across interconnected brain regions are influenced by the brain’s connectome and a specific genetic risk factor for AD, i.e., ApoE4. Overall, these findings enrich our understanding of tau's progression within the cortex and carries implications for individualised approaches in determining the timing and target of therapeutic interventions
Virus infections as risk factors in the development of bronchopulmonary dysplasia (BPD)
Get PDFBronchopulmonary dysplasia (BPD) is a multifactorial chronic lung disease primarily affecting premature infants, often resulting from the complex interplay of preterm birth, mechanical ventilation, and oxygen therapy. The complicated relationship between inflammation, oxidative stress, and impaired lung growth contributes to the development of this challenging condition. The immune system of prematurely born children, often referred to as preterm or premature infants, is underdeveloped compared to those born at full term. Premature birth and the associated underdeveloped respiratory system render affected infants more susceptible to various infections. Viral infections in infants with BPD often manifest with heightened severity, posing a substantial challenge in clinical management. Virus infections represent a significant global health concern, affecting millions of individuals annually and posing a substantial burden on healthcare systems. Gammaherpesviruses, a subgroup of the Herpesviridae family, encompass notable pathogens such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). These viruses present significant health concerns due to their association with various cancers and their intricate evasion strategies against the host immune system. Both EBV and KSHV can cause severe respiratory complications in individuals with compromised immune systems. A key challenge in studying human herpesviruses is the absence of a dependable small animal model for investigating fundamental aspects of viral pathogenesis. Murine gammaherpesvirus 68 (MHV-68) serves as a naturally occurring virus genetically related to human gammaherpesviruses, including EBV and KSHV. My study addressed the impact of MHV-68 infection on the development of BPD in one of the major lung cell types – fibroblasts: CCL-206 and neonatal primary mouse lung fibroblasts (in vitro part). This investigation presents novel outcomes resulting from early postnatal exposure to clinically significant hyperoxia concentrations (FiO2 = 0.4, 24 hours) with the following MHV-68 infection.
A significant finding in this study was the observed impact of O2 treatment (FiO2 = 0.4), leading to a noteworthy decrease in Caspase 3/7 activity, necrosis, and proliferation in primary fibroblasts. Importantly, this effect occurred without any discernible changes in cell morphology. The study suggests that hyperoxic conditions potentially trigger adaptive mechanisms in primary fibroblasts within the initial 24 hours post-exposure, moderating apoptosis and necrosis without altering cell morphology. Conversely, MHV-68 infection resulted in a substantial increase in necrosis and a decrease in apoptosis, proliferation, and cell migration capabilities. The infected cells exhibited reduced Pdgfrα gene expression, elevated Vegf gene expression, and irreversible morphological changes, indicative of potential cell-cycle arrest. Virus replication curve was significantly lower in cells exposed to hyperoxia, this finding demonstrated decreased proliferation of exposed cells. Notably, CCL-206 cells, being immortalized, displayed increased Caspase 3/7 activity, potentially attributed to their artificial ability for continuous proliferation. I conducted an investigation utilizing TGFβ stimulation on CCL-206 cells and primary fibroblasts to assess its potential influence on MHV-68 infection, juxtaposing its effects with those resulting from hyperoxia exposure. TGFβ treatment elicited distinct impacts on cellular responses and MHV-68 infection. Specifically, within the initial 24-hour post-virus infection period, TGFβ treatment exhibited no alterations in necrosis or apoptosis in fibroblasts, and it did not induce changes in cellular proliferation and migration. Owing to the disparate signaling pathways engaged, TGFβ cannot serve as a suitable comparative control for in vitro hyperoxia studies.
Exploring BPD, we aimed to develop a clinically relevant animal model for studying lifelong consequences. The study employed a double-hit model involving hyperoxia exposure (FiO2 = 0.4) and MHV-68 infection in neonatal mice, revealing significant changes in Radial Alveolar Count (RAC) and septal wall thickness of the adult mice, indicating altered lung morphology after mice were treated in the early days of life, emphasizing the mutual influence nature of hyperoxia and viral infection injuries in adult alveoli. MHV-68 titer in lungs was significantly increased in mice prior exposed to hyperoxia, indicating the enhanced immune response in lung cells due to the preliminary hyperoxia exposure. The study's exploration of sex-related differences uncovered notable variations in lytic MHV-68 titer, RAC, and alveolar wall thickness between male and female mice, adding an additional layer of complexity to the interplay of infection, hyperoxia, and BPD
Klimawandel und mentale Gesundheit von Kindern und Jugendlichen in Deutschland
Get PDFZielsetzung:
Klimawandel und insbesondere EWE haben einen Einfluss auf die psychische Gesundheit von Kindern und Jugendlichen. Wie diese Auswirkungen jedoch in Deutschland konkret aussehen und versorgt werden, ist bislang nicht erforscht. Im Rahmen von zwei Studien wurden Daten zu emotionalen Reaktionen und psychischen Erkrankungen, beide ausgelöst durch das Erleben von EWE, deren Risiko- und protektiven Faktoren sowie zur Versor-gungssituation in Deutschland erhoben.
Materialien und Methoden:
Im quantitativen Teil des Projektes wurde eine deutschlandweite Befragung zu den psychi-schen Auswirkungen von EWEs, deren Einflussfaktoren sowie zu Methoden der Prävention, Früherkennung und Versorgung durchgeführt. Der Fragebogen wurde sowohl durch medi-zinisches und therapeutisches Personal als auch durch schulisches und pädagogisches Personal beantwortet. Insgesamt wurden 648 vollständig ausgefüllte Fragebogen mit Hilfe von R 4.2.1 ausgewertet.
Im qualitativen Teil des Projektes wurden neun semi-strukturierte Interviews mit Vertre-ter*innen der versorgenden Berufsgruppen von Kindern und Jugendlichen in einer von ei-ner Überflutung betroffenen Stadt vorgenommen. Darin beantworteten die Befragten Fra-gen zu den beobachteten Auswirkungen der Überflutung auf die psychische Gesundheit der Kinder und Jugendlichen inklusive deren Einflussfaktoren und ihre Erfahrungen mit der Versorgung der jungen Bevölkerungsgruppe. Die Interviews wurden anhand der qualitati-ven Inhaltsanalyse nach Mayring mit Hilfe von MAXQDA 2020 ausgewertet.
Ergebnisse:
Psychische Erkrankungen, die mit dem Klimawandel assoziiert sind, werden nach Einschät-zung der Befragten in Deutschland in Zukunft zunehmen. Insbesondere die direkte Betrof-fenheit, die psychische Vorbelastung sowie der Verlust der Alltagsstruktur stellen relevante Stressoren für die psychische Gesundheit dar. Protektive Faktoren sind Gespräche mit Be-zugspersonen über das Erlebte, das Einbeziehen der Kinder und Jugendlichen in die Auf-räumarbeiten und der schnelle Wiederaufbau. Die Versorgung betroffener Kinder und Ju-gendlichen wird insbesondere durch ihre Eltern oder andere familiäre Bezugspersonen übernommen. Auch Personen aus ihrem alltäglichen Umfeld, wie Lehrer*innen und Trai-ner*innen können diese Rolle übernehmen und ergänzen.
Diskussion:
Junge Menschen werden im Laufe ihres Lebens immer häufiger EWE ausgesetzt sein und dadurch in ihrem psychischen Wohlbefinden beeinträchtigt werden. Kinder und Jugendliche können mit der richtigen Unterstützung ihre Resilienz gegenüber diesen Auswirkungen ge-zielt steigern. Die Hilfestellungen nach dem Erleben eines EWE sollten insbesondere über ihre Bezugspersonen erfolgen. Unabhängig ob im privaten oder beruflichen Rahmen sollten ihnen die dafür notwendigen Ressourcen zur Verfügung gestellt werden.Purpose:
Climate change and especially EWE have an impact on the mental health of children and adolescents. To date, research is lacking on what these mental health-effects look like and how they are treated in Germany. Within the framework of two studies, data on emotional reactions and mental illnesses triggered by the experience of EWE, their risk and protective factors as well as data on the care situation in Germany were collected.
Materials and Methods:
In the quantitative part of the project, a Germany-wide questionnaire was conducted with questions on the psychological effects of EWEs, their influencing factors, and methods of prevention, early detection, and care. This was answered by medical and therapeutic staff as well as by school and pedagogical staff. A total of 648 fully completed questionnaires were evaluated using R 4.2.1.
In the qualitative part of the project, nine semi-structured interviews were conducted with professionals caring for children and adolescents in a city affected by flooding. In these, interviewees answered questions about the observed impact of flooding on mental health of children and adolescents including influencing factors and their experiences of providing care to the young population group. The interviews were analyzed according to Mayring's qualitative content analysis using MAXQDA 2020.
Results:
Mental illnesses associated with climate change will increase in Germany in the future ac-cording to the estimation of the respondents. Direct exposure to EWE, psychological pre-load, and loss of everyday structure are relevant stressors for mental health. Protective fac-tors are conversations with relatives about the experience, involvement of children and ado-lescents in the clean-up work and rapid reconstruction. The care of affected children and adolescents is taken over by their parents or other caregivers. People from their everyday environment, such as teachers and trainers, can also take on this role.
Discussion:
Young people will be exposed to EWE with increasing frequency throughout their lives, af-fecting their mental well-being. However, with the appropriate support, children and adoles-cents can increase their resilience to these impacts. Providing support after experiencing an EWE should be done especially through their caregivers. Whether in a private or profes-sional setting, caregivers should be provided with the necessary resources to do so
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