Preclinical characterization of molecular hallmarks of Huntington's Disease through dynamic PET imaging
13 november 2019
UAntwerp - Campus Drie Eiken - Building O - Auditorium O3 - Universiteitsplein 1 - 2610 WILRIJK (route: UAntwerpen, Campus Drie Eiken
Prof S. Staelens & Prof J. Verhaeghe
PhD defence Daniele Bertoglio - Faculty of Medicine and Health Sciences
Presentation in English
Huntington’s disease (HD) is a rare, autosomal dominant inherited neurodegenerative disorder caused by an expanded polyglutamine sequence in the huntingtin gene (HTT), which encodes for mutant huntingtin (mHTT), the causative agent of the disorder. The genetic mutation responsible for the disorder has been identified in 1993, recently marking the 25 years from its discovery. Since then, research has tremendously advanced in the characterization of the natural disease progression, identification of underlying molecular mechanisms, and assessment of potential endpoints for the evaluation of the efficacy of therapeutic interventions. Although a number of candidate therapeutic approaches aimed at lowering mHTT are underway, their development and evaluation are hindered by the lack of objective in vivo markers to assess the efficacy of these therapeutic strategies. In this context, positron emission tomography (PET) imaging could represent a prime non-invasive in vivo tool for direct assessment of alterations in a number of relevant proteins.
In this thesis we aimed to provide a substantial contribution in the selection of preclinically valuable non-invasive PET markers to investigate candidate biomarkers for monitoring of HD-related disease progression for future disease-modifying therapeutic interventions.
A total of six radioligands quantifying five different proteins were investigated in the knock-in Q175 mouse model of HD. Prior to applying each PET radioligand in extensive longitudinal studies, we performed a thorough methodological validation to assure application of the most suited imaging protocol in order to achieve accurate quantification.
All the investigated biomarkers were found to be affected during disease progression in HD mice. The assessment of phosphodiesterase 10A (PDE10A) with [18F]MNI-659 PET imaging resulted in a profound decline of the binding in HD mice. Quantification of the Group I metabotropic glutamate receptors type 1 (mGluR1) and type 5 (mGluR5) (using [11C]ITDM and [11C]ABP688, respectively) identified differential profiles in HD mice. Synaptic vesicle glycoprotein 2A (SV2A), measured with [11C]UCB-J, provided non-invasive evidence for a progressive synaptic decline affecting mutation carrier mice. Finally, non-invasive quantification of mHTT accumulation was performed for the first time in the brain of HD mice using two different radioligands. Remarkably, both radioligands proved high capability in measuring mHTT accumulation during natural disease progression.
In conclusion, this work established a preclinical imaging platform and identified the most suited markers for assessment of disease-modifying therapies in order to aid the future translation from bench-to-bedside.