Systems Biology Approaches for Identification of Molecular Mechanisms in Brain Disorders

Doctoral thesis (2018)

One out of four people are affected by a brain disorder at some stage in their life. Depending on the symptoms and the underlying molecular mechanisms, brain disorders can be classified into neurological ... [more ▼]

One out of four people are affected by a brain disorder at some stage in their life. Depending on the symptoms and the underlying molecular mechanisms, brain disorders can be classified into neurological and cognitive disorders. Complex disorders typically have a multifactorial pathogenesis. Epilepsy and postoperative delirium (POD) exemplifying neurological and cognitive disorders are no exception. Research efforts contributed to the understanding of molecular mechanisms of these diseases by discovering associations between clinical and genomic information and disease phenotypes. These findings, although necessary, are not sufficient to reconstruct the complete map of system-level interactions. To achieve a system-level understanding of a biological system, one can integrate diverse data sources by a network-based approach. Network analysis methods characterise interactions within and between molecular systems and can identify candidate biomarkers in various biological contexts. Specifically, correlation networks can reveal condition-dependent molecular patterns whose functional enrichment points to the altered molecular mechanisms of the phenotype. A molecular signature of a phenotype can be determined by machine learning algorithms for supervised classification as a set of molecules accurately discriminating between disease and healthy state. The primary aim of this dissertation is to identify altered biological pathways and functionally relevant molecules of epileptogenesis and postoperative delirium. This cumulative dissertation is composed of six chapters. Chapter 1provides the background information on brain disorders and the systems biology methods to study their molecular mechanisms. Chapter 2 was motivated by the fact that current anti-epilepsy treatments focus on minimisation of the symptoms and epileptic seizures, while no definitive cure exists. The understanding of molecular events triggering the development of epilepsy (also called epileptogenesis) can yield therapies halting the onset of epilepsy. We identified proteomic alterations in the animal model of epileptogenesis by a network-based method and validated our results by external data set and immunohistochemical staining. The functional annotation of molecular expression patterns revealed biological pathways not yet described in the context of epileptogenesis. Next, we identified the gap in a comparative analysis of available antiepileptic drugs for mesial temporal lobe epilepsy due to hippocampal sclerosis. Chapter 3 retrospectively compares retention, efficacy and tolerability of antiepileptic drugs in the large epilepsy pharmacogenomics database. Chapter 4 is focused on the identification of molecular alterations in postoperative delirium. Overlaying postmortem brain expression data with locations of functional networks disturbed in POD, we identified several gene expression patterns with relevant biological enrichment. Moreover, same biological functions were altered in the blood of POD patients. Previously described POD markers such as acetylcholinesterase, alpha-synuclein and protein C appeared in the identified clusters. In Chapter 5, I focused on the identification of a molecular signature discriminating POD patients before they undergo surgery. Having ranked preoperative expression levels of mRNAs and miRNAs by their ability to detect patients with POD, I identified a set of discriminatory features that achieved high accuracy, sensitivity and specificity in the training set. The trained model had a good generalisability on the unseen data set but its performance decreased on the test set not matched by age and gender. The final Chapter 6 summarises the main outcomes of the presented studies and concludes with an outlook. [less ▲]

Comparative effectiveness of antiepileptic drugs in patients with mesial temporal lobe epilepsy with hippocampal sclerosis

in Epilepsia (2017)

Objective: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a common epilepsy syndrome that is often poorly controlled by antiepileptic drug (AED) treatment. Comparative AED ... [more ▼]

Objective: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a common epilepsy syndrome that is often poorly controlled by antiepileptic drug (AED) treatment. Comparative AED effectiveness studies in this condition are lacking. Wereport retention, efficacy, and tolerability in a cohort of patients with MTLE-HS. Methods: Clinical data were collected from a European database of patients with epilepsy. We estimated retention, 12-month seizure freedom, and adverse drug reaction (ADR) rates for the 10 most commonly used AEDs in patients with MTLE-HS. Results: Seven hundred sixty-seven patients with a total of 3,249 AED trials were included. The highest 12-month retention rates were observed with carbamazepine (85.9%), valproate (85%), and clobazam (79%). Twelve-month seizure freedom rates varied from 1.2% for gabapentin and vigabatrin to 11% for carbamazepine. Response rates were highest for AEDs that were prescribed as initial treatment and lowest for AEDs that were used in a third or higher instance. ADRs were reported in 47.6% of patients, with the highest rates observed with oxcarbazepine (35.7%), topiramate (30.9%), and pregabalin (27.4%), and the lowest rates with clobazam (6.5%), gabapentin (8.9%), and lamotrigine (16.6%). The most commonly reported ADRs were lethargy and drowsiness, dizziness, vertigo and ataxia, and blurred vision and diplopia. Significance: Our results did not demonstrate any clear advantage of newer versus older AEDs. Our results provide useful insights into AED retention, efficacy, and ADR rates in patients with MTLE-HS. [less ▲]

Analysis of the dynamic co-expression network of heart regeneration in the zebrafish

in Scientific Reports (2016), 6

The zebrafish has the capacity to regenerate its heart after severe injury. While the function of a few genes during this process has been studied, we are far from fully understanding how genes interact ... [more ▼]

The zebrafish has the capacity to regenerate its heart after severe injury. While the function of a few genes during this process has been studied, we are far from fully understanding how genes interact to coordinate heart regeneration. To enable systematic insights into this phenomenon, we generated and integrated a dynamic co-expression network of heart regeneration in the zebrafish and linked systems-level properties to the underlying molecular events. Across multiple post-injury time points, the network displays topological attributes of biological relevance. We show that regeneration steps are mediated by modules of transcriptionally coordinated genes, and by genes acting as network hubs. We also established direct associations between hubs and validated drivers of heart regeneration with murine and human orthologs. The resulting models and interactive analysis tools are available at http://infused.vital-it.ch. Using a worked example, we demonstrate the usefulness of this unique open resource for hypothesis generation and in silico screening for genes involved in heart regeneration. [less ▲]

Biomarkers of postoperative delirium and cognitive dysfunction

in Frontiers in Aging Neuroscience (2015), 7(112),

Elderly surgical patients frequently experience postoperative delirium (POD) and the subsequent development of postoperative cognitive dysfunction (POCD). Clinical features include deterioration in ... [more ▼]

Elderly surgical patients frequently experience postoperative delirium (POD) and the subsequent development of postoperative cognitive dysfunction (POCD). Clinical features include deterioration in cognition, disturbance in attention and reduced awareness of the environment and result in higher morbidity, mortality and greater utilization of social financial assistance. The aging Western societies can expect an increase in the incidence of POD and POCD. The underlying pathophysiological mechanisms have been studied on the molecular level albeit with unsatisfying small research efforts given their societal burden. Here, we review the known physiological and immunological changes and genetic risk factors, identify candidates for further studies and integrate the information into a draft network for exploration on a systems level. The pathogenesis of these postoperative cognitive impairments is multifactorial; application of integrated systems biology has the potential to reconstruct the underlying network of molecular mechanisms and help in the identification of prognostic and diagnostic biomarkers. [less ▲]

Network-based Approach Enabling Drug Repositioning for the Treatment of Myocardial Infarction

Bachelor/master dissertation (2014)

Despite a notable reduction in incidence of acute myocardial infarction (MI), patients who experience it remain at risk for premature death and cardiac malfunction. The human cardiomyocytes are not able ... [more ▼]

Despite a notable reduction in incidence of acute myocardial infarction (MI), patients who experience it remain at risk for premature death and cardiac malfunction. The human cardiomyocytes are not able to achieve extensive regeneration upon MI. Remarkably, the adult zebrafish is able to achieve complete heart regeneration following amputation, cryoinjury or genetic ablation. This raises new potential opportunities on how to boost the heart healing capacity in humans. The objective of our research is to characterize the transcriptional network of the zebrafish heart regeneration, to describe underlying regulatory mechanisms, and to identify potential drugs capable to boost heart regeneration capacity. Having identified the gene co-expression patterns in the data from a zebrafish cryoinjury model, we constructed a weighted gene co-expression network. To detect candidate functional sub-networks (modules), we used two different network clustering approaches: a density-based (ClusterONE) and a topological overlap-based (Dynamic Hybrid) algorithms. We identified eighteen distinct modules associated with heart recovery upon cryoinjury. Functional enrichment analysis displayed that the modules are involved in different cellular processes crucial for heart regeneration, including: cell fate specification (p-value < 0.006) and migration (p-value < 0.047), cardiac cell differentiation (p-value < 3E-04), and various signaling events (p-value < 0.037). The visualization of the modules’ expression profiles confirmed the relevance of these functional enrichments. Among the candidate hub genes detected in the network, there are genes relevant to atherosclerosis treatment and inflammation during cardiac arrest. Among the top candidate drugs, there were drugs already reported to play therapeutic roles in heart disease, though the majority of the drugs have not been considered yet for myocardial infarction treatment. In conclusion, our findings provide insights into the complex regulatory mechanisms involved during heart regeneration in the zebrafish. These data will be useful for modeling specific network-based responses to heart injury, and for finding sensitive network points that may trigger or boost heart regeneration in the zebrafish, and possibly in mammals. [less ▲]