Research Daniele Bertoglio

Abstract

Spinal cord injury (SCI) is a devastating condition characterized by long-term motor and sensory neurological deficits, severely affecting the life of patients and their families. Although emerging therapeutic strategies focused on functional recovery are being explored, their development and translation to clinical use are severely limited by the lack of functional, objective, and non-invasive imaging biomarkers. Without quantifiable prognostic biomarkers, the clinical heterogeneity between SCI patients limits healthcare workers' qualitative measure of the potential future functional recovery. Using clinically relevant rat models, we propose a multimodal neuroimaging approach focused on synaptic and white matter markers to determine the prognostic and predictive outcome of (non)traumatic SCI. Longitudinal imaging with positron emission tomography (PET, for synaptic marker) and magnetic resonance imaging (MRI, for inflammation and white matter integrity) will be used for the establishment of a multimodal imaging platform to define lesions affecting the spinal cord to ultimately provide meaningful information related to lesion severity, functional outcome, and predictive value in a therapeutic context. Our platform will facilitate the interpretation of therapeutic results in preclinical studies, supporting the identification of most responsive treatment approaches and thus lowering the risks and costs for pharmaceutical companies' interest in the clinical translation of SCI.

Researcher(s)

• Promoter: Bertoglio Daniele
• Co-promoter: Verhoye Marleen
• Fellow: Schrauwen Claudia

Research team(s)

• Bio-Imaging lab

Project type(s)

• Research Project

Abstract

Huntington's disease (HD) is a rare, autosomal dominant inherited neurodegenerative disorder caused by an expanded polyglutamine sequence in the huntingtin gene (HTT) encoding for mutant huntingtin (mHTT). HD neuropathology is characterized by basal ganglia neurodegeneration, leading to progressive motor, psychiatric, and cognitive impairments, and ultimately death. While the pathogenic mechanisms by which mHTT causes selective dysfunction of the medium-size spiny neurons (MSNs) in the basal ganglia remain uncertain, we have extensive (pre)clinical evidence on the progressive loss of both D1 receptors (D1R) and D2 receptors (D2R), involved in direct and indirect dopaminergic pathways, respectively. Although MSN degeneration occurs roughly in equal proportions for D1R and D2R, the indirect dopaminergic pathway is affected first, resulting in the occurrence of the involuntary movements (hyperkinesia) characteristic of HD. As of today, there is a substantial knowledge gap in understanding the relationship between dopaminergic receptor density and the functional signalling of both direct and indirect dopaminergic pathways. In this project, a multimodal approach will be applied consisting of advanced non-invasive functional magnetic resonance imaging (fMRI), electrophysiology, behaviour, and post-mortem techniques in HD mouse models, with specific modulation of the direct or indirect dopamine pathway. The outcome will increase our understanding of the functional integrity of both dopaminergic pathways of the basal ganglia in HD.

Researcher(s)

• Promoter: Bertoglio Daniele
• Fellow: Decrop Marion

Research team(s)

• Bio-Imaging lab

Project type(s)

• Research Project

Abstract

Traumatic spinal cord injury (SCI) is a devastating condition characterized by long-term motor and sensory neurological deficits. The functional loss in patients with SCI is mostly dictated by the precise anatomical location, with injuries to the cervical region accounting for nearly 50% of the patients with SCI, and the extent of damage at the spinal level, with contusion injuries being the most frequent. Although emerging therapeutic strategies focused on functional recovery after SCI are being explored, their development and translation to clinical use are severely limited by the lack of functional, objective, and noninvasive in vivo imaging biomarkers related to pathophysiological processes, thus reflecting the underlying SCI damage, functional outcome, and repair mechanisms. The goal of this project is to establish synaptic and white matter integrity changes, two key pathophysiological hallmarks of SCI, as in vivo biomarkers for monitoring and predicting SCI outcomes. In a clinically relevant cervical contusion rat model of SCI, we will apply state-of-the-art MRI and synaptic PET neuroimaging in a longitudinal multimodal approach to visualize and quantify synaptic and white matter integrity over time. In vivo imaging data will be complemented by behavioural tests and ultrasensitive detection of blood biomarkers to correlate molecular or cellular changes with functional motor deficits. In combination with post-mortem analyses, this provides an extremely powerful paradigm for the interpretation of the biomarker findings in relation to the underlying mechanisms and functional outcomes. The unique position of this multidisciplinary proposal is embraced by the investigation of in vivo noninvasive multimodal imaging biomarkers of key pathophysiological processing occurring during SCI in a clinically ready set-up. Accurate quantitative imaging biomarkers will facilitate the interpretation of therapeutic results in preclinical studies, ensuring a faster translation of promising new treatment strategies to patients with SCI.

Researcher(s)

• Promoter: Bertoglio Daniele

Research team(s)

• Bio-Imaging lab

Project type(s)

• Research Project

Abstract

During the past decades, many traditional medical imaging techniques have been established for routine use. These imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), and radionuclide imaging (PET/SPECT) are widely applicable for both small animal and clinical imaging, diagnosis and treatment. A unique feature of molecular imaging is the use of molecular imaging agents (either endogenous molecules or exogenous tracers) to image particular targets or pathways and to visualize, characterize, and quantify biological processes in vivo. Dedicated high-resolution small animal imaging systems such as microPET/CT scanners have emerged as important new tools for preclinical research. Considerable benefits include the robust and non-invasive nature of these small animal imaging experiments, enabling longitudinal studies with the animal acting as its own control and reducing the number of laboratory animals needed. This approach of "miniaturised" clinical scanners efficiently closes the translational feedback loop to the hospital, ultimately resulting in improved patient care and treatment. By this underlying submission, our consortium aims to renew our 2011 microPET/CT scanners after their ten-year lifetime by a digital up-to-date system in order to continue our preclinical molecular imaging studies in several research fields, including neuroscience, oncology and tracer development.

Researcher(s)

• Promoter: Staelens Steven
• Co-promoter: Augustyns Koen
• Co-promoter: Bertoglio Daniele
• Co-promoter: Elvas Filipe
• Co-promoter: Stroobants Sigrid
• Co-promoter: Van Der Veken Pieter
• Co-promoter: Verhaeghe Jeroen

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

Abstract

Huntington's disease (HD) is a dominantly inherited disorder characterized by a progressive neurodegeneration of the striatum that also involves other regions, primarily the cerebral cortex. Patients display progressive motor, cognitive, and psychiatric impairment. Symptoms usually start at midlife. The mutation responsible for this fatal disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin. The pathogenic mechanisms by which mutant huntingtin cause neuronal dysfunction and cell death remain uncertain (Menalled, 2005). The mechanism underlying HD-related suppression of inhibition has been shown to include tonic activity of metabotropic glutamate receptor subtype 5 (mGluR5) as a pathophysiological hallmark (Dvorzhak, Semtner, Faber, & Grantyn, 2013) and inhibition of glutamate neurotransmission via specific interaction with mGluRs might be interesting for both inhibition of disease progression as well as early symptomatic treatment (Scheifer et al., 2004). With the objective to elucidate the role of glutamatergic pathways using small animal PET imaging, this study aims to use several PET imaging agents as tracers in a knock-in model of Huntington's disease.

Researcher(s)

• Promoter: Staelens Steven
• Co-promoter: Bertoglio Daniele
• Co-promoter: Van Der Linden Annemie
• Co-promoter: Verhaeghe Jeroen
• Co-promoter: Verhoye Marleen

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

Abstract

Daniele Bertoglio graduated with the highest honours in Pharmaceutical Biotechnology at the University of Bologna, Italy in November 2014, after performing his master thesis at the Robert Wood Johnson Medical School in New Jersey, USA. Immediately after, he began working as a Ph.D. researcher in Medical Sciences at the University of Antwerp in December 2014 and successfully obtained an FWO Ph.D. fellowship in 2015. His doctoral studies exploited the use of positron emission tomography (PET) imaging as a prime non-invasive in vivo tool for direct assessment of alterations in several molecular targets in preclinical models of Huntington's Disease (HD) to characterize non-invasively dynamic molecular changes occurring at key stages of HD progression. His research pioneers the field of PET imaging of mutant huntingtin (mHTT) aggregates in active preparation for human biomarker studies in longitudinal follow-up of patients and clinical candidate therapies, providing an outstanding contribution to the field of Molecular Imaging for HD. His research included multimodality imaging techniques as well as robust post-mortem assessment to unravel novel candidate markers for HD, which have resulted in excellent contributions in high-impact peer-reviewed international journals and the Ph.D. in Medical Sciences defended at the University of Antwerp in November 2019. His scientific interest and passion for preclinical neuroimaging led him to pursue a second Ph.D. in Biomedical Sciences investigating the process of epileptogenesis in preclinical models of acquired epilepsy using different studies combining magnetic resonance imaging (MRI) and PET imaging which was successfully defended at the University of Antwerp in June 2021. In addition, Daniele obtained an FWO postdoc position, and he is working as a postdoctoral researcher at MICA, University of Antwerp. He uses various translational neuroimaging tools to quantify structural, functional, and molecular changes in preclinical models of neurological diseases, focusing on Huntington's disease, temporal lobe epilepsy, and spinal cord injury. His research applies state-of-the-art small animal neuroimaging techniques, including MRI and PET imaging, to identify novel candidate biomarkers to monitor disease progression, predict disease outcome, and evaluate the efficacy of innovative therapeutic approaches. To date, Daniele has co-authored a total of 23 original peer-reviewed publications in international journals, of which 14 as the first author, and contributed to 2 book chapters.

Researcher(s)

• Promoter: Bertoglio Daniele

Research team(s)

• Bio-Imaging lab
• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

Abstract

Huntington's disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by mutant huntingtin (mHTT). Patients with HD exhibit progressive motor and cognitive decline, and development of psychiatric symptoms. Pathological features of HD include wide-spread progressive accumulation of mHTT, selective neurodegeneration, and forebrain atrophy. The synaptic vesicle glycoprotein 2A (SV2A) is a vesicle membrane protein expressed ubiquitously in synapses of the brain, involved in neurotransmitter release. SV2A can be used as a proxy to measure synaptic density in vivo using the radioligand [11C]UCB-J and positron emission tomography (PET). Based on our in vivo [11C]UCB-J PET imaging and in vitro [3H]UCB-J autoradiography findings in HD mice, demonstrating SV2A decline, we hypothesize the levels of SV2A to be decreased in patients with HD as a direct effect of mutant huntingtin accumulation as well as by the consequent neurodegeneration occurring with disease progression. Thus, the objective of this project is to provide evidence for the clinical significance of SV2A as a candidate biomarker in patients with HD in comparison to age- and gender-matched healthy non-demented subjects using in vitro autoradiography and immunohistochemistry in post-mortem samples from patients with HD and healthy subjects. The knowledge derived from this project will not only contribute to supporting the preclinical outcomes, filling the gap between preclinical and clinical findings, but it will represent a significant contribution in supporting SV2A as a candidate imaging biomarker for disease progression to be investigated in longitudinal SV2A PET imaging studies in patients with HD.

Researcher(s)

• Promoter: Bertoglio Daniele

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

Abstract

Huntington's Disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by a genetic mutation in the huntingtin gene (HTT), which encodes for mutant huntingtin (mHTT), the causative agent of the disorder. Since lowering the levels of toxic mHTT is postulated to halt disease progression, the use of engineered zinc finger protein transcription repressors (ZFP-TR) to selectively suppress the mutant HTT allele represents a novel candidate treatment for HD. A major limitation in the assessment of therapeutic efficacy is the lack of objective non-invasive markers. We recently validated the first-ever radioligand to image in vivo mHTT levels using positron emission tomography (PET) imaging in mice. The aim of this project is to assess the preclinical relevance of the use of ZFP-TR at different disease stages as candidate therapeutic intervention. This work will provide proof of efficacy for an mHTT lowering HD therapy in the living (rodent) brain by measuring mHTT in parallel to molecular targets for phenotypic recovery in wellcharacterized mouse models of HD. This multi-modal approach consisting of non-invasive in vivo PET imaging in combination with magnetic resonance imaging (MRI) and post-mortem techniques will represent a strategic multi-disciplinary platform to assess the efficacy of the ZFP-TR therapeutic efficacy providing a key contribution on the timing of intervention, ultimately leading to clinical translation in the future. GENERAL -

Researcher(s)

• Promoter: Staelens Steven
• Co-promoter: Verhaeghe Jeroen
• Fellow: Bertoglio Daniele

Research team(s)

• Molecular Imaging and Radiology (MIRA)

Project type(s)

• Research Project

Abstract

Epilepsy is a devastating disorder affecting 65 million people worldwide characterized by recurrent seizures. This research project will investigate a novel hypothesis connecting translocator protein (TSPO) overexpression, a hallmark of brain inflammation, and spontaneous seizure outcome during the development of epilepsy (epileptogenesis). Our hypothesis is supported by the observation that i) TSPO is highly up-regulated in epilepsy and ii) our preliminary data suggest a relationship between TSPO overexpression and spontaneous seizure outcome. Unraveling this relationship will enable us to assess TSPO as a biomarker for maladaptive neuroplasticity during epileptogenesis. Firstly, by means of translational techniques, we will investigate longitudinally the pattern of TSPO expression during epileptogenesis in vivo in the kainic acid-induced status epilepticus (KASE) model. Secondly, the role of TSPO in epileptogenesis will be investigated by the study of the effects of the absence of TSPO in the TSPO knockout mouse, and by pharmacological stimulation of TSPO in the KASE model. This innovative project will increase our understanding of brain excitability during epileptogenesis offering a biomarker to identify patients at risk and moving the field forward giving a contribution to the development of therapies to prevent acquired epilepsy.

Researcher(s)

• Promoter: Verhaeghe Jeroen
• Co-promoter: Staelens Steven
• Fellow: Bertoglio Daniele

Research team(s)

Project type(s)

• Research Project

Abstract

Epilepsy is a devastating disorder affecting 65 million people worldwide characterized by recurrent seizures. This research project will investigate a novel hypothesis connecting translocator protein (TSPO) overexpression, a hallmark of brain inflammation, and spontaneous seizure outcome during the development of epilepsy (epileptogenesis). Our hypothesis is supported by the observation that i) TSPO is highly up-regulated in epilepsy and ii) our preliminary data suggest a relationship between TSPO overexpression and spontaneous seizure outcome. Unraveling this relationship will enable us to assess TSPO as a biomarker for maladaptive neuroplasticity during epileptogenesis. Firstly, by means of translational techniques, we will investigate longitudinally the pattern of TSPO expression during epileptogenesis in vivo in the kainic acid-induced status epilepticus (KASE) model. Secondly, the role of TSPO in epileptogenesis will be investigated by the study of the effects of the absence of TSPO in the TSPO knockout mouse, and by pharmacological stimulation of TSPO in the KASE model. This innovative project will increase our understanding of brain excitability during epileptogenesis offering a biomarker to identify patients at risk and moving the field forward giving a contribution to the development of therapies to prevent acquired epilepsy.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie
• Promoter: Verhaeghe Jeroen
• Co-promoter: Dedeurwaerdere Stefanie
• Co-promoter: Verhaeghe Jeroen
• Fellow: Bertoglio Daniele

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Epilepsy is a devastating disorder affecting 50 million people worldwide characterised by recurrent seizures and serious psychiatric comorbidities such as anxiety and depression. This research proposal will investigate a novel hypothesis connecting brain inflammation and neurosteriod alterations as protagonists during the development of epilepsy and its comorbidities a process termed epileptogenesis. These former pathways are shown to have bimodal effects on seizure susceptibility, but up till now have only been investigated independently. Our hypothesis of coupling these pathways is supported by the observation that i) the translocator protein (TSPO) a marker of brain inflammation is highly upregulated in epilepsy and ii) the main function of TSPO is cholesterol import, the rate-limiting step in steroidogenesis. Firstly, we will for the first time investigate the brain region and cell specific distribution pattern of TSPO during epileptogenesis and established epilepsy in two rat models of acquired epilepsy. Secondly, pharmacological agents will be used to interfere with TSPO and brain inflammation to investigate a causal relationship between TSPO and epileptogenesis by means of translational techniques namely in vivo TSPO PET imaging, behavioural tests and video-EEG monitoring in a rat model of temporal lobe epilepsy. This innovative project will increase our understanding of the ambiguous complexities related to brain inflammation- and neurosteriod-induced effects on brain excitability potentially revealing an interrelated action. If the proposed hypothesis holds true, this may influence our current thinking regarding the role of brain inflammation in epilepsy and psychiatric conditions.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie
• Fellow: Bertoglio Daniele

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project