Senne Heeren

• 1 juli 2025, 16u - 18u
• Aula Janssens (ITG)
• Promotoren: Jean-Claude Dujardin, Frederik Van den Broeck, Philippe Lemey

Eva Govarts

• 28 mei 2025, 16u - 18u
• Promotiezaal, Q.002 (CDE)
• Promotoren: Greet Schoeters, Roel Vermeulen

Abstract (Engels)

Throughout their lifetime, humans are exposed to a plethora of environmental stressors including environmental pollutants like hazardous chemicals that independently or in interaction may have an impact on health. As chemical risk assessment typically evaluates single compounds and often single-exposure pathways, it generally does not reflect the complexity of concomitant exposure to multiple chemicals in real life. There is growing evidence that adverse birth outcomes are associated with prenatal exposure to different pollutants.

The aim of this thesis was to add to the weight of evidence linking prenatal exposure to environmental pollutants with adverse birth outcomes and as such inform risk assessment taking into account real life exposures through birth cohort studies that have measured different occurring exposures as well as effect markers. We employed some state-of-the-art statistical methods for estimating chemical, chemical mixtures and mediation effects on early life health outcomes.

Overall, our findings add to the scientific weight of evidence that prenatal environmental exposure to compounds with the capacity to alter hormonal homeostasis (endocrine disruptors), such as some organochlorine compounds, PFAS and metals may contribute to adverse birth outcomes. The direction of the estimates differed by chemicals, suggesting diverse mechanisms of action and biological pathways. Moreover, our results add to the mechanistic evidence that hormonal markers are on the causal path in the association between environmental exposure and fetal growth.

These research findings inform and improve chemical risk assessment. The multi-pollutant methods we applied in this thesis allow exposure-outcome estimation and improve risk assessment in a real-life context. The influence of prenatal environmental exposure on adverse birth outcomes, advocates for policy actions to be taken (i.e., development of adequate regulations) and sensibilization of pregnant women (through clinicians, healthcare professionals, etc.) on how to avoid or reduce exposure to persistent organic pollutants, metals and PFAS. By understanding these risks and sources of exposure, informed decisions can be taken to minimize exposure of pregnant women, protect their health and that of their children. Our results contributed to expand and integrate the internal and external exposome in epidemiological studies and to elucidate the underlying causal path as the biological mechanism, to disentangle and identify the chemical drivers and covariates that have most impact on health. Doing so, this thesis is a step forward towards a more holistic approach.

Evelien Van Dijck

• 26 mei 2025, 11u - 13u
• Promotiezaal, Q.002 (CDE)
• Promotoren: Wim Van Hul, Wim Vanden Berghe

Abstract (Engels)

Obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) are complex diseases with multifactorial etiologies. Their prevalence is continuously rising and poses a huge burden on human health and health-care systems. Although recent breakthroughs for therapeutic targets have been established in both diseases, the pathophysiological disease mechanisms remain elusive, limiting the development of precise and effective biomarkers, prognostic tools and treatment strategies. To address these issues, this thesis presents targeted genetic and untargeted epigenetic analyses aimed at elucidating the mechanisms and key players involved. Chapters 3 and 4 of this thesis focus on rare variants, which have a presence of less than 1% in the general population, but might significantly contribute to disease heritability on a population scale. In Chapter 3, we examined the association between the rare p.Y181H proprotein convertase subtilisin/kexin type 1 (PCSK1) variant and obesity in a case-control setup. We found no difference in carrier frequency between the two cohorts, indicating that in our cohort, the variant did not contribute to obesity susceptibility. Chapter 4 investigates a family of anti-inflammatory and anti-oxidative genes with high expression in the liver. This paraoxonase (PON) gene family comprises three members: PON1, PON2 and PON3. Using targeted sequencing, we identified a PON1 SNP that was associated with MASLD-associated fibrosis. Additionally, rare variants in PON1 and PON2 were associated with obesity and MASLD-related fibrosis, respectively. Although genetic research refines our understanding of the genetic architecture of obesity and MASLD, genetics alone can't explain the rapidly rising obesity and MASLD rates. Important factors such as environment and lifestyle contribute to disease development and progression and influence gene expression through epigenetic mechanisms like DNA methylation (DNAm). As such, Chapter 5 constitutes the second part of this thesis, where epigenetic marks, specifically DNAm, were explored in MASLD patients using an untargeted approach. We identified that changes in liver DNAm occur in a gradual fashion during MASLD progression. Additionally, epigenetic age acceleration (EAA), a measure of biological aging, showed significant correlation with MASLD progression, indicating biomarker potential. Further integrated downstream analysis combining DNAm, gene expression data and network analysis for both MASLD and EAA measures identified numerous transcription factors (TFs) related to metabolism, immune function and redox homeostasis. As a result, our study highlights the potential of these TFs to be used as biomarkers and/or therapeutic targets in the future.

Mandy Melissa Jane Wittens

• 17 maart 2025, 15u - 17u
• Auditorium O1 (CDE)
• Promotoren: Sebastiaan Engelborghs, Maria Bjerke

Abstract (Engels)

Alzheimer’s disease (AD) is a global health challenge influenced by genetic, lifestyle, and environmental factors. Though its precise onset remains unclear, AD is characterized by amyloid-β plaques, tau tangles, and neuronal loss, leading to cognitive impairments. The adoption of a clinical-biological biomarker framework enables earlier intervention and personalized treatment, driving research toward refining biomarkers for improved diagnosis and prognosis.

Magnetic resonance imaging (MRI) biomarkers, including medial temporal lobe atrophy (MTA), hippocampal volume reduction, and ventricular enlargement, are valuable for detecting brain changes. Traditionally, manual segmentation has been the gold standard, but automated volumetric tools using machine learning are now enhancing accuracy and efficiency. This study evaluates icobrain dm, an automated brain volumetry tool for clinical MRI scans, assessing its feasibility for routine clinical integration. By addressing validation, standardization, and biomarker integration challenges, this research aims to enhance AD detection, staging, and management, supporting personalized treatment strategies.

Our findings show that icobrain dm demonstrates robust intra- and inter-scanner reliability (mean DSC > 0.88) and high reproducibility (mean CV < 3%) across global, cortical, and subcortical structures. Icobrain’s automated MTA assessment, expressed as the ratio between inferior lateral ventricle and hippocampal volumes, correlates strongly with visual MTA ratings across cognitive decline stages. However, automated hippocampal volumes alone exhibit moderate correlation, highlighting the inferior lateral ventricle's crucial role in MTA assessment. Comparing automated MTA scores with age-matched healthy controls could aid in clinical interpretation of medial temporal atrophy severity.

Additional findings suggest icobrain dm enhances diagnostic certainty by assessing hippocampal and temporal cortex volumes in AD. Brain age and Brain-Predicted Age Difference (BPAD) correlate with accelerated brain aging beyond chronological age and classify cognitive states effectively. Notably, heavy alcohol consumption accelerates brain aging, as reflected in significant BPAD differences between heavy drinkers and non-drinkers.

The development of event-based models (EBMs) for AD staging has shown promising generalizability and reliability across datasets. Notably, amnestic Mild Cognitive Impairment (MCI) subjects exhibit higher biomarker event scores than non-amnestic MCI, improving precision in clinical trial recruitment.

Additionally, analysis of white matter hyperintensity (WMH), neuropsychological scores, and hippocampal volumes underscores the complex relationship between WMH and cognitive function.

Despite progress, challenges remain in validating automated measurements across diverse populations. Tailored EBMs for AD subtypes are crucial for accurate staging, and further research is needed to interpret the interplay between WMH load and cognitive outcomes. Addressing these challenges will enhance the adoption of automated MRI analysis, improving AD diagnosis and patient care.

Angela Sisto

• 3 februari 2025, 16u - 18u
• Promotiezaal, Q.002 (CDE)
• Promotor: Vincent Timmerman

Abstract (Engels)

Autophagy is a vital cellular process that recycles damaged organelles and protein aggregates, maintaining cellular health in peripheral neurons and muscle fibers. Triggered by nutrient deprivation or stress, autophagy relies on molecular chaperones and specialized receptors to identify and transport damaged components (cargo) to autophagosomes. These vesicles then fuse with lysosomes, where the cargo is degraded and recycled. Impairments in this pathway contribute to the pathogenesis of several diseases.

This thesis explores the genetic and molecular mechanisms underlying autophagy dysfunction in inherited peripheral neuropathies and congenital disorders of the skeletal and cardiac muscle. Mutations in small heat shock proteins HSPB1 and HSPB8 are major causes of Charcot-Marie-Tooth neuropathies (CMT type 2) and distal hereditary motor neuropathies (dHMN). These mutations disrupt autophagy, leading to protein aggregation and cellular dysfunction.

In particular, the HSPB1 P182L mutation exerts a toxic gain-of-function on the autophagy receptor SQSTM1/p62, reducing its oligomerization and mobility upon autophagy stimulation. This results in decreased autophagosome formation and contributes to protein stress and neuronal damage in CMT2F models. Similarly, the HSPB8 K141N mutation reduces autophagosome formation, pointing to a common pathogenic mechanism across these mutations.

Using a cellular model carrying the HSPB8 K141N mutation and fluorescent autophagy markers, a phenotypic drug screen identified novel autophagy inducers capable of rescuing autophagy deficits. Validation in patient-derived motor neurons, differentiated from induced pluripotent stem cells carrying HSPB1 and HSPB8 mutations, showed significant improvements in neuronal health upon treatment.

These findings highlight the pathological overlap between motor neuron and muscle diseases and identify key steps in the autophagy pathway disrupted by HSPB mutations. By uncovering novel molecular targets and pharmacological modulators. Furthermore, this work provides a foundation for developing therapies to restore autophagy and mitigate neurodegeneration in CMT and other autophagy-related diseases.

Souleymane Hassane Harouna

• 9 januari 2025, 16u - 18u
• Aula Janssens (ITG)
• Promotoren: Leen Rigouts, Bouke de Jong

Abstract (Engels)

Tuberculosis (TB) is a contagious disease caused by the Mycobacterium tuberculosis complex (MTBc) posing a global health challenge, particularly with drug-resistant TB (DR-TB) detection and treatment. Indeed, despite global efforts, only about 43% of DR-TB cases are diagnosed and treated, with a 68% treatment success rate for the World Health Organization (WHO) 2021 cohort. This thesis aimed to enhance the diagnosis and management of multidrug-resistant TB (MDR-TB) in Guinea by testing novel diagnostic approaches and improving therapeutic strategies. To achieve our objectives, we conducted two diagnostic studies and to therapeutic studies Chapter II explored face mask sampling (FMS) as a minimally invasive method for pulmonary TB diagnosis among symptomatic patients. FMS results, compared to sputum samples analyzed by the Xpert MTB/RIF and Xpert MTB/RIF Ultra (Xpert Classic and Xpert Ultra), showed moderate agreement (kappa value of 0.47), with overall low sensitivity (48.1%) but high specificity (95.7%). While Xpert Ultra yielded higher sensitivity than Xpert Classic (60.2% vs 38.0%), Xpert Classic had superior specificity (100% vs 90.6%).

Following these mitigated results, we explored in Chapter III tongue swabbing (TS) with Xpert Ultra and in-house swab IS6110-qPCR as another minimally invasive diagnostic approach. In a prospective study, single TS showed lower sensitivity (88.5%) than sputum, although pooling swabs improved sensitivity to 93.8%. Furthermore, bacillary load of positive TS samples was not affected by the sampling order, and "MTB low" results were predominant for both single and pooled series of TS. Sample adequacy control via qPCR assay detected human mitochondrial DNA and thus confirmed the oral source of TS samples. In a retrospective analysis, the agreement between the in-house swab IS6110-qPCR and sputum-Xpert was high (k=0.91 for Xpert Classic and k=0.86 for Ultra).

Chapter IV  addressed MDR-TB treatment with a longer regimen (lasting 18-20 months) and a shorter regimen (9-11 months) outcomes in a post-Ebola setting. Results showed that patients on a shorter regimen were more likely to achieve successful treatment outcome (74.0% vs. 58.7%) and less likely to experience adverse events (loss to follow-up, death or treatment failure), with a two-fold increase in risk for those on a longer regimen (aOR: 2.5).

In Chapter V, community supported self-administered TB treatment (CS-SAT) and active TB screening among household contacts were evaluated. CS-SAT achieved a 94.7% favorable outcome, exceeding the national target of 90%. Active household screening enabled the referral of 376 children for isoniazid preventive therapy and the detection of five pulmonary confirmed TB among household contacts.

Our studies contributed to enhancing TB diagnosis and treatment. Findings suggest that further diagnostic studies using the new sampling approches are need for pulmonary TB diagnosis. Children and paucibacillary group patients should be prioritized for such studies. For MDR-TB treatment, shorter regimens should be prioritized. Additionally, enhancing the technical capacity of laboratories and medical services is crucial to ensure improved outcomes. Finally, community-supported TB treatment should be tailored to specific contexts and patient needs, to guarantee the continuity of the patient treatment.