Development of Quantitative PET Imaging Probes for Neuroinflammation

Lead Research Organisation: King's College London
Department Name: Neuroimaging

Abstract

Inflammation is a protective attempt by the immune response of the organism to remove the injurious stimuli as well as to initiate the healing process for the tissue. The inflammatory process is generally beneficial but an inflammation that runs unchecked can also lead to a host of diseases, such as hay fever, atherosclerosis, and rheumatoid arthritis. It is for this reason that inflammation is normally closely regulated by the body.
The brain and spinal cord are considered ?immune privileged? tissues in that they are separated from the rest of the body by a series of endothelial cells known as the blood-brain barrier, which prevent most infections from reaching the vulnerable nervous tissue. For this reason, inflammation in the CNS (Neuroinflammation) is mediated by a unique cell type, microglia. Microglia are part of the non-neuronal part of the cell population in the brain called glia, the other glial cell being the astrocytes and the oligodendrocytes. Quiescent microglia have a ramified morphology as they are constantly moving and analyzing the CNS for damaged neurons, plaques, and infectious agents; whenever an anomaly is detected, microglia enter an active state and undergo several morphological changes including the thickening and retraction of branches, the expression of immunomolecules, the secretion of cytotoxic factors, recruitment molecules and pro-inflammatory signaling molecules.
Microglial activation is therefore present early in any pathological state of the brain and the in-vivo detection of microglial activation is a key diagnostic aim. Besides, microglia chronic activation has also been suggested as a key factor in the inception and/or progression of neurodegenerative diseases like Alzheimer?s disease and Parkinson?s disease. This project aims at delivering an optimal imaging biomarker for microglia using Positron Emission Tomography (PET) technology. PET is a Nuclear Medicine modality that is able to image the distribution of radioactive labelled compounds. The interest in imaging microglia with PET radiotracers is such that more than 50 radiotracers targeting microglia are now proposed world-wide. In the context of this training proposal, we will test the most promising PET microglia tracers, devise appropriate data-processing procedures and metrics that will allow the selection of the optimal marker to be used in the future in diagnostics, research and drug development.

Technical Summary

The main aim of this research proposal is to shape a Post-Graduate Training Program in PET Methodology focused on the mathematical modelling of novel TSPO tracers in the normal and diseased brain. The TSPO is consistently expressed in the active microglia population in response to mild, acute or chronic brain injury. Microglia are the resident immuno-competent cell of the central nervous system and, in their active state, release pro-inflammatory molecules that initiate and sustain the immune response. This state is generally referred to as ?Neuroinflammation?. Microglia activity is not only regarded as the most sensitive marker of brain disease but it has also been proposed as pathogenic agent in neurodegenerative diseases, Alzheimer?s and Parkinson?s disease in particular. In-vivo TSPO imaging using PET started more than 20 years ago using 11C-PK11195, a positron emitter labelled antagonist for the TSPO but, because of the poor sensitivity of this tracer, research for novel TSPO tracers has surged in the last 5 years with more than 50 new PET TSPO-markers under various stages of clinical validation. It is because of this exceptionally large number of novel tracers and the importance of neuroinflammation for the clinical neurosciences that we define as the main objective of the proposed training program the identification of the optimal TSPO PET probe(s) and of the associated quantitative methodology.
The training program is proposed in three phases. The first one (3 months) will provide the trainee with the basic knowledge on PET methodology. The second phase, (21 months) will consist in a set of 3 months supervised research projects, that will look at various aspects(biological/pathology/chemical/kinetic) of novel TSPO ligands and supply data to a metric (the elaboration of which is one of the research questions) that will inform on the best amongst all candidates and on its quantification procedure. The last phase of the research program (24 months) will be carried out independently by the trainee in the field of TSPO data quantification and will make use of the wealth of clinical and pre-clinical data available at the participating PET centres. We believe that this proposal has unique strengths in the form and content of the training program, in the relevance of the theme for the neurosciences, in the quality and breadth of experience in PET Methodology of the proponents, and the strong academic/industrial partnership (Imperial/GSK) that characterizes the environment.

Publications

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Albrecht DS (2018) Pseudoreference Regions for Glial Imaging with C-PBR28: Investigation in 2 Clinical Cohorts. in Journal of nuclear medicine : official publication, Society of Nuclear Medicine

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Edison P (2013) Microglia, amyloid, and glucose metabolism in Parkinson's disease with and without dementia. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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García-Lorenzo D (2018) Validation of an automatic reference region extraction for the quantification of [F]DPA-714 in dynamic brain PET studies. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

 
Title Neuroscience and Graphic Design 
Description This is a digital image library to improve peer-to-peer scientific graphical communication 
Type Of Art Artefact (including digital) 
Year Produced 2017 
Impact Linked to this initiative we organised a set of workshop to improve the creation of scientific and conceptual figures. A description of the event is reported here: https://neuroscience-graphicdesign.com/workshops/ 
URL https://neuroscience-graphicdesign.com
 
Description Glaxo Smithkline - Excellence in Imaging Centre
Amount £400,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 07/2017 
End 08/2019
 
Description Innovative Medicine Initiative (IMI)
Amount € 8,838,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 11/2016 
End 10/2021
 
Description New Investigator Research Grant
Amount £459,272 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2016 
End 05/2019
 
Description Strategic Award: Neuroinflammation in Alzheimer's Disease and Depression
Amount £1,720,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 12/2019
 
Description Targeting neuroinflammation in schizophrenia
Amount £841,703 (GBP)
Funding ID MR/N027078/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description Wellcome Trust Consortium for Neuroimmunology of Mood Disorders and Dementia (NIMA).
Amount £5,000,000 (GBP)
Funding ID 104025/Z/14/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2017 
End 12/2018
 
Title Biomathematical modelling approach 
Description This modelling approach is developed to predict the in vivo performance of radioligands from in vitro/in silico data. 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact This model assisted experimental design for TSPO imaging by estimating the in vivo reproducibility of the radioligand and the sample sizes/power required by the experiment. 
 
Title PK modelling 
Description Different pharmacokinetic models have been applied in the analysis of in vivo PET data. 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact Different models were used to quantify to TSPO binding in human brain in healthy volunteers and MS patients, and specifically the double input models identified the metabolite issues with tracers. 
 
Title Statistical tool for PET experimental design 
Description A statistical modelling approach to estimate sample size required for longitudinal and disease characterisation studies using PET. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2011 
Provided To Others? Yes  
Impact The methods have been used to assist in the experimental design of more than 8 in vivo PET studies on neuroinflammation. 
 
Title in vivo PET scans wit 18F-PBR111 
Description These PET scans were funded by GSK and performed by GSK and Imanova, which allows for the evaluation of different quantification methodology of TSPO imaging. 
Type Of Material Biological samples 
Provided To Others? No  
Impact These vivo imaging data is the first time in human data that TSPO/neuroinflammation that has been detected using 18F-PBR111. This tracer produced higher total signal than the traditional tracer 11C-PK11195. The in vivo uptake is consistent with genetics. 
 
Title in vivo PET study with 11C-PBR28 
Description in vivo PET scans using 11C-PBR28 with arterial blood samples 
Type Of Material Biological samples 
Provided To Others? No  
Impact The in vivo TSPO uptake is consistent with genetics 
 
Description Aarhus Hospital 
Organisation Aarhus University Hospital
Country Denmark 
Sector Academic/University 
PI Contribution We analysed the PET data using the SUPERPK approach developed by our team.
Collaborator Contribution Aarhus Hospital provided us clinical PET data of patients who has spinal cord injury;
Impact In vivo PET data has been analysed to investigate the inflammation associated with spinal cord injury. This is a multi-disciplinary collaboration as it covers area of medicine, neurology, imaging and quanfication.
Start Year 2010
 
Description Dr. Paolo Zanotti-Fregonara (University of Bordeaux, Fr) 
Organisation Houston Methodist Research Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution Dr. Zanotti-Fregonara shared with us his PET datasets (acquired in collaboration with National Institutel of Mental Health). With this data we had the opportunity to test and validate some of the new modelling approaches for quantification of neuroinflammation PET tracers that are currently in use for