Isabel Cuella Martin 

• 23 October 2025, 4pm - 6pm
• Aula Janssens (ITG)
• Promoters: Leen Rigouts, Bouke de Jong

Jolien Perneel 

• 15 October 2025, 4pm - 6pm
• Promotiezaal, Q.002 (CDE)
• Promoter: Rosa Rademakers

Abstract

This thesis explores the multifaceted role of TMEM106B as a genetic modifier in neurodegenerative diseases and healthy aging. TMEM106B was first identified as a risk-modifying locus in frontotemporal lobar degeneration (FTLD), with particularly strong effects in carriers of pathogenic GRN variants. Since then, accumulating evidence has established TMEM106B as a key modulator of disease risk, clinical presentation, and cognitive resilience across a spectrum of neurodegenerative disorders. TMEM106B encodes a glycosylated, type II transmembrane protein predominantly localized to late endosomes and lysosomes, compartments that are essential for cellular waste processing and protein homeostasis. Importantly, common polymorphisms at the TMEM106B locus form distinct haplotypes that confer either protective or deleterious effects on neurodegenerative processes. This thesis investigates TMEM106B as a modifier of both disease and healthy aging through a combination of genetic, molecular, and neuropathological approaches.

Particularly in the context of FTLD caused by GRN mutations, we provide evidence that the TMEM106B risk haplotype acts as a permissive allele. GRN carriers with two protective haplotypes may remain asymptomatic, while individuals without the risk haplotype who nonetheless develop disease often have a later disease onset, present with atypical disease symptoms, or harbor additional genetic risk factors. These findings suggest that they may have a different disease etiology. To address underlying mechanisms, we generated a transgenic mouse model overexpressing human TMEM106B. Elevated TMEM106B levels disrupted lysosomal function, induced synaptic and behavioral abnormalities, and promoted age-dependent hippocampal neurodegeneration, thereby implicating TMEM106B in neuronal vulnerability during aging independent of overt disease. Recent cryo-electron microscopy studies revealed that the TMEM106B C-terminal fragment (CTF; residues 120–254) forms amyloid fibrils in the brain of individuals with diverse neurodegenerative disorders and in neurologically normal elderly. Our work extends these findings by showing that the burden of TMEM106B CTF aggregates correlates with age and TMEM106B risk haplotype and that FTLD-TDP cases with GRN mutations have a particularly high burden of these aggregates. Although the aggregates were widely distributed across cell types and brain regions, they did not colocalize with other pathological proteins, suggesting a distinct pathological pathway.

Overall, this thesis demonstrates that TMEM106B appears to play a dual role in brain health: elevated levels promote lysosomal dysfunction and neuronal vulnerability, while the protective haplotype preserves lysosomal integrity and resilience. These findings position TMEM106B as a central modulator of lysosomal biology, neurodegenerative risk, and brain aging, and highlight the importance of incorporating TMEM106B genotyping into both research and clinical settings.

Farhan Ul Haq 

• 30 September 2025, 4pm - 6pm
• Auditorium O2 (CDE)
• Promoters: Guy Van Camp, Geert Vandeweyer, Ken Op de Beeck

Abstract

Chromosomal rearrangements are common oncogenic drivers in non-small cell lung cancer (NSCLC). Among them, fusions involving the ROS1 kinase domain produce constitutively active proteins that can be effectively targeted by tyrosine kinase inhibitors (TKIs). Despite initial therapeutic benefit, treatment response is frequently compromised by resistance-conferring point mutations. The underlying structural mechanisms remain poorly understood, primarily due to the lack of experimentally determined structures for ROS1 mutants, despite the availability of ROS1 wild-type models. Additionally, structural data for the inactive (DFG-out) conformation is also lacking, which is essential for studying kinase-specific TKIs.

To address this gap, we generated ROS1 models through homology modelling using closely related kinases. These models enabled detailed investigation of type I and type II inhibitor interactions using molecular docking. Furthermore, by using molecular dynamics simulations, we examined allosteric mutations (L1982F, S1986F, S1986Y) and found that, although distal to the ATP binding pocket, they modulate binding pocket volume via alterations in G-loop dynamics. We also characterized clinically relevant ATP-site mutations (L2026M, G2032R, L2086F), which displayed distinct changes in A-loop and the G-loop flexibility as well as αC-helix orientation.

Moreover, analysis of the F2004C/V mutations revealed a unique mechanism of resistance to type II TKIs. While these variants preserved the active conformation, they destabilized the inactive state by altering the flexibility of DFG residue (F2103) and reinforcing the hydrophobic cluster. This difference also explains their varying sensitivity to type I versus type II inhibitors.

To integrate computational and experimental evidence, we investigated G2032R, L2026M, and S1986Y variants in patient-derived ROS1 positive cell lines (CUTO-28, CUTO-37) generated with CRISPR/Cas9. Drug sensitivity profiling using dose–response assays and immunoblotting of phosphorylated ROS1 (Tyr2274), combined with docking and MD simulations, highlighted variant-specific responses to multiple TKIs, including crizotinib, ceritinib, lorlatinib, entrectinib, and repotrectinib.

Our findings provide a comprehensive overview of the structural and functional consequences of ROS1 kinase domain mutations. Besides, by highlighting how specific substitutions alter kinase conformations and vary inhibitor binding, this study also enhances the mechanistic understanding of ROS1 drug resistance and supports the development of more effective targeted therapies.

Claudio D'Incal 

• 25 September 2025, 4pm - 6pm
• Auditorium O5 (CDE)
• Promoter: Frank Kooy

Abstract

Neurodevelopmental disorders, such as autism spectrum disorder and intellectual disability, are a major societal challenge, affecting over 3% of children worldwide and profoundly impact the lives of patients and their families. This doctoral research focuses on two frequent autistic syndromes with intellectual disability: Helsmoortel-Van der Aa syndrome and fragile X syndrome.

De novo variants in the Activity-Dependent Neuroprotective Protein (ADNP) gene are among the most frequent causes of autism and show complete disease penetrance. However, the function of ADNP protein in the brain remains poorly understood. Using complementary detection strategies, we showed that truncating ADNP variants were absent in patient-derived materials, while stably expressed in overexpression systems. To investigate brain-specific effects, we developed a novel Adnp heterozygous mouse model carrying a patient-like frameshift variant. Molecular and behavioural profiling revealed disrupted pathways linked to neurodevelopment. Since no curative treatment is available, we tested the ADNP-derived investigational drug NAP (davunetide) in three Adnp mouse models with distinct mutations, aiming to restore abnormal pathways and behaviours. To validate translational relevance, we analysed post-mortem brain tissue from a child with an ADNP variant, that supported findings from in vitro and in vivo models. Overall, these studies provide important insights into ADNP protein biology and identify potential therapeutic strategies.

Fragile X syndrome is the most common inherited cause of autism and intellectual disability. It is caused by CGG repeat expansion in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, resulting in silencing of the FMRP protein, a regulator of synaptic mRNA translation. While preclinical studies have shown to be beneficial, the outcomes of clinical trials remain inconsistent. To identify new therapeutic targets, we applied kinome profiling in hippocampal tissue from Fmr1 knockout and wild-type mice. We observed globally increased kinase activity, with strong effects in insulin receptor (InsR) signalling. Hyperphosphorylation of Akt1, GSK3α/β, IRS1, and p70S6K was confirmed by phospho-arrays and mass spectrometry, alongside disruption of the Akt-Erk1-mTOR axis. Pathway analysis indicated altered neuronal development, migration, and postsynaptic organization. Drug-connectivity mapping nominated novel kinase inhibitor as a promising therapeutic compound.

Collectively, we established new translational models, clarified molecular disease mechanisms, and identified candidate therapeutic strategies. Together, these findings provide a foundation for developing targeted treatments for patients with ADNP- and FMR1-related disorders.

Kayhan Ilbeigi

• 8 September 2025, 4pm - 6pm
• Promotiezaal, Q.002 (CDE)
• Promoter: Guy Caljon
  

Abstract

Animal trypanosomiasis (AT) is a vector-borne parasitic disease caused by multiple Trypanosoma species, including T. congolense, T. vivax, T. brucei brucei, T. b. evansi, and T. b. equiperdum. Affecting livestock across Africa, Asia, and Latin America, AT undermines food security, rural development, and economic stability in endemic regions. Despite its vast socioeconomic burden, the disease remains critically neglected, with limited investment in drug development. Treatment still relies on a small arsenal of decades-old trypanocides, which suffer from toxicity, limited efficacy, and rising drug resistance. Given the lack of prophylactic vaccines and the emergence of resistant strains, novel, safe, and broad-spectrum therapeutics are urgently needed.

This thesis aimed to (i) evaluate and characterize novel antitrypanosomal compounds with efficacy across multiple Trypanosoma species, and (ii) implement a One Health drug discovery framework that integrates early safety and environmental profiling. Nucleoside analogues were chosen as the chemical class of interest, leveraging the purine auxotrophy of African trypanosomes and the success of nucleoside-based drugs in oncology, virology, and parasitology.

Among the tested candidates, two compounds emerged as promising leads. 3′-Deoxytubercidin, a 7-deazaadenosine analogue with potent activity against both stages of HAT, achieved sterile cure in murine models of Surra (T. b. evansi) and Dourine (T. b. equiperdum). It was also evaluated with preliminary ecotoxicity tests using Daphnia magna and Desmodesmus subspicatus, indicating a relatively low environmental risk profile. However, this compound did not undergo mechanistic or genotoxicity assessments within the scope of this thesis.

The second lead, 6-thiophenyl 7-deazapurine riboside analogue (FH15967/compound 3), showed submicromolar in vitro activity against major AT-causing species, including T. vivax. The compound demonstrated excellent metabolic stability and successfully cured multiple AT infections in mouse models. Mechanistic studies identified the parasite’s adenosine kinase (ADKIN) as essential for drug activation and suggested P1-type nucleoside transporters as primary uptake routes. Comparative metabolomic profiling further supported intracellular phosphorylation as a prerequisite for activity. In addition to efficacy and mode-of-action, FH15967 underwent early safety evaluations, including three in vitro genotoxicity assays (Vitotox®, micronucleus, and Comet), all confirming a lack of DNA-damaging potential. Ecotoxicological testing of FH15967 showed no significant toxicity to aquatic indicator species, supporting alignment with One Health sustainability goals.

In summary, this thesis advances nucleoside analogues as a promising therapeutic class for treating AT. Through systematic evaluation of their efficacy, safety, and environmental impact, the research provides a strong foundation for continued development aligned with One Health principles.

Mahamadou Bassirou Souleymane Tiemogo

• 3 September 2025, 10am - 12am
• Aula Janssens (ITG)
• Promoters: Leen Rigouts, Bouke de Jong, Tom Decroo

Abstract

Tuberculosis (TB) remains a critical global health challenge. In 2023, it reclaimed its position as the leading cause of death from a single infectious agent. That year, nearly half a million people were infected with multidrug-resistant (MDR) or rifampicin-resistant (RR) TB. MDR-TB refers to bacteria that are resistant to isoniazid and rifampicin, the two most powerful first-line TB drugs, yet only 40% of these cases were diagnosed and treated. Treatment success rates reflect this challenge. While 88% of new TB patients were successfully treated in 2023, this dropped to 78% among retreatment TB patients and just 68% among those with MDR TB. In Niger, a resource-limited setting with high TB burden, diagnostic gaps and limited access to drug susceptibility testing (DST) exacerbate the crisis.

My PhD research focused on managing difficult-to-treat TB in Niger, particularly recurrent rifampicin-susceptible (Rs)-TB, RR-TB and recurrent RR-TB. Conducted during the COVID-19 pandemic, my work integrated public health responses, including simultaneous TB/COVID-19 screening, which proved effective in detecting TB.

To address recurrent Rs-TB, we conducted the TRIDORE clinical trial, which compared a novel six-month regimen of the four first-line drugs using triple doses of rifampicin and isoniazid (6R3H3ZE), with the standard-dose six-month (6RHZE) regimen. Although the triple-dose approach was intended to overcome undetected isoniazid resistance in the absence of DST, it resulted in significantly more severe adverse events and was deemed not recommended for programmatic use.

For RR-TB, we evaluated Niger’s adaptive short treatment regimen, which contains a second-line injectable drug. This is replaced with linezolid if any ototoxicity is detected at baseline or during monthly audiometry tests. The approach was compared with the WHO-recommended all-oral 9-month regimen containing bedaquiline and linezolid. Both regimens showed comparable efficacy, but the adaptive short treatment regimen in Niger had significantly fewer severe adverse events, which supports its use and suggests that tailoring treatment based on individual tolerance can mitigate toxicity without compromising efficacy, even when using injectable drugs that are typically considered poorly tolerated.

Finally, we studied a cascade treatment approach for patients with recurrent RR-TB following an unfavourable outcome on a fluoroquinolone-based short treatment regimen. Retreatment with a bedaquiline-based regimen led to a high relapse-free cure, ensuring no patient was left without effective treatment options.

This thesis shows that context-adapted, safety-conscious treatment strategies supported by pragmatic designs and programmatic flexibility are essential in high-burden, low-resource settings for TB and RR-TB control.

Joke Temmerman 

• 3 September 2025, 5pm - 7pm
• Promotiezaal, Q.002 (CDE)
• Promoters: Sebastiaan Engelborghs, Miguel D'haeseleer, Maria Bjerke

Abstract

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, and degenerative disease of the central nervous system and the leading cause of non-traumatic neurological disability in young to middle-aged adults. Despite the efficacy of disease-modifying treatments (DMTs) in reducing relapses and lesion accumulation, many patients experience disability progression independent of relapses. This underscores the need for reliable biomarkers that capture subtle disease processes to improve monitoring and support individualized treatment.

The aim of this thesis was to investigate neuroinflammatory and neurodegenerative biomarkers associated with MS worsening, using clinically representative, real-world cohorts. Both fluid- and imaging-based biomarkers were evaluated for their prognostic potential and applicability in clinical practice.

Our results showed that brain volume loss (BVL), measured via MRI, was comparable between patients meeting the “no evidence of disease activity-3” criteria under high-efficacy DMT and healthy controls, whereas patients with evidence of disease activity exhibited a 72% higher BVL rate. This suggests that timely initiation of effective therapy may reduce neurodegeneration to levels seen in physiological aging.

In another longitudinal MRI study, gray matter (GM) atrophy rate was significantly associated with worsening manual dexterity and composite disability scores, despite no overall difference in BVL between MS patients and controls. These findings underscore the clinical relevance of GM-specific measures while also highlighting technical challenges that currently limit the implementation of BVL metrics in routine care.

Finally, serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NF-L) were jointly evaluated in a clinically representative cohort. Patients with elevated serum levels of both markers showed greater BVL than those with NF-L elevation alone, indicating that GFAP provides complementary information on neurodegeneration. GFAP was associated with both global and regional brain atrophy, whereas NF-L was more specifically related to GM volumes, suggesting distinct spatial patterns of pathology.

In conclusion, our research supports a multimodal biomarker framework that integrates imaging and fluid measures to more comprehensively monitor the overlapping but distinct processes of inflammation and neurodegeneration in MS. Addressing current methodological and technical barriers will be essential for implementing these findings into routine clinical practice.

Lalita Roy

• 2 September 2025, 5pm - 7pm
• Aula Janssens (ITG)
• Promoters: Wim Van Bortel, Guy Caljon, Epco Hasker

Abstract

Visceral leishmaniasis (VL), also known as kala-azar, is targeted for elimination as a public health problem from the Southeast Asia (SEA) region, including Nepal, by 2030. In Nepal, the national VL elimination programme initially identified 12 districts as endemic (classical endemic districts), situated in the eastern and central lowlands. The country achieved the elimination target of reducing the annual disease rate to less than 1 new case per 10,000 population in these 12 endemic districts in 2013. In the following years, the programme encountered some emerging challenges. Outbreaks were reported from areas where disease control strategies have been implemented for years, and the VL cases spread in high-altitude areas, which were previously assumed unsuitable for Leishmania transmission. Being a vector-borne disease, multiple factors associated with the host (human), vector (Phlebotomus argentipes sand flies), and pathogen (Leishmania donovani) need to be evaluated to understand the root causes of this evolution. In this thesis, we focused on generating information on key indicators associated with the vector, which were either limited or lacking.

The key entomological indicators including the peaks of vector sand fly density in summer months (June to November), presence of the vector infected with the parasite, and the human being as the preferred host, reflected the persistent L. donovani transmission in the classical endemic districts. This study also highlighted the threat of insecticide resistance in vector sand flies against pyrethroids in Nepal, where pyrethroid-based indoor residual spraying has been the sole vector control intervention for the last three decades. Further investigation suggested that both genetic and metabolic resistance mechanisms likely contribute to the observed pyrethroid resistance. In addition, we explored the presence of vector species in newly affected areas to evaluate the potential of local transmission. We found vector species in the majority of the surveyed districts with recent VL cases, irrespective of their endemicity status. We also demonstrated, for the first time in Nepal, the potential use of the mitochondrial cytochrome c oxidase subunit I (COI) gene as a molecular marker for the sand fly species identification.

All major entomological indicators corroborated the ongoing L. donovani transmission in classical endemic and other districts with recent VL cases. Hence, continued vigilance and supply of disease and vector control interventions in all its implementation units are essential requisites to achieve and sustain the VL elimination from the country in the scheduled date.

Senne Heeren

• 1 July 2025, 4pm - 6pm
• Aula Janssens (ITG)
• Promoters: Jean-Claude Dujardin, Frederik Van den Broeck, Philippe Lemey

Abstract

Biological interactions are a key component in the maintenance of our ecosystems and nature in general, where all species interact with at least one other species. However, the effect of these interactions, or symbioses, is not always beneficial to all parties. Take viruses for example. Whether or not they are considered organisms, viruses are infectious agents of virtually all life forms on our planet and are well known for their direct impact on plant, animal and human populations. However, there are other viruses that may cause more complex and indirect effects on populations through the infection of other organisms (e.g. bacteria or protozoa) that are, in turn, pathogenic to others (e.g. humans). In these cases, the presence of viruses may complicate the pathogen’s disease dynamics in the host, leading to more severe disease outcomes, treatment failure or symptomatic relapse. These types of viruses were able to remain under the radar for a long time but have been increasingly detected over the past twenty-five years.

One of the best-established examples of such a virus-parasite interaction is the one between Leishmania parasites and Leishmaniavirus (LRV). Here, LRV and Leishmania appear to have a mutualistic relationship where the virus facilitates parasite survival through interaction with the host’s immune response – leading to increased disease progression, exacerbation, and treatment failure – in exchange for the exploitation of proteins required for viral replication and survival.  Because of these potentially adverse pathological effects, it becomes important to account for the presence of these viruses in the context of the control and elimination of diseases like leishmaniasis.

The work presented in this thesis was performed to gain a better understanding of the eco-epidemiology and evolutionary history of Leishmania parasites through the lens of their unique microbial alliance with LRV. This revealed two novel findings: (i) the compelling evidence of a strong co-evolutionary history between the virus and parasite across the different taxonomic levels of both Leishmania and LRV; and (ii) the multifaceted importance of Leishmania hybridization in the eco-epidemiology of leishmaniasis and its apparent association with maintaining the genetic diversity of LRV as well as its distribution. With this, our work strongly highlights the need for large-scale and continuous surveillance of pathogens, especially those causing neglected tropical diseases, and raises the importance of research on symbioses in general.

Eva Govarts 

• 28 May 2025, 4pm - 6pm
• Promotiezaal, Q.002 (CDE)
• Promoters: Greet Schoeters, Roel Vermeulen

Abstract

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 May 2025, 11am - 1pm
• Promotiezaal, Q.002 (CDE)
• Promoters: Wim Van Hul, Wim Vanden Berghe

Abstract

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 March 2025, 3pm - 5pm
• Auditorium O1 (CDE)
• Promoters: Sebastiaan Engelborghs, Maria Bjerke

Abstract

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 February 2025, 4pm - 6pm
• Promotiezaal, Q.002 (CDE)
• Promoter: Vincent Timmerman

Abstract

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 January 2025, 4pm - 6pm
• Aula Janssens (ITG)
• Promoters: Leen Rigouts, Bouke de Jong

Abstract

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.