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INMIND Report Summary

Project ID: 278850
Funded under: FP7-HEALTH
Country: Germany

Periodic Report Summary 4 - INMIND (Imaging of Neuroinflammation in Neurodegenerative Diseases)

Project Context and Objectives:
The INMiND project focuses on the study of molecular mechanisms of neuroinflammation (NI) in neurodegenerative diseases (ND) with the aim to identify novel biomarkers for activated microglia for both diagnostic and therapeutic purposes.
Neurodegenerative diseases such as Alzheimer’s (AD), Parkinson’s (PD) or Huntington’s Disease (HD), Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS) are among the most common chronic neurological disorders with devastating consequences not only for patients and their families (impaired cognition, motor function and activities of daily living) but also on a societal and socioeconomic level (early labour force dropout and increased burden on health care system). These diseases have in common that protein turn-over is impaired leading to deposition of extra- and/or intra-cellular protein aggregates, which induces recruitment and activation of immune system cells (microglia). These reactive microglia are involved both in inflammation-mediated neurotoxicity as well as in neuroregenerative repair mechanisms, depending on disease stage and cell polarisation status (M1 or M2 phenotype).
Microglial responsiveness to injury suggests that it may serve as marker for disease activity and progression and represents a target for diagnostic and/or therapeutic purposes. The INMiND project focuses on cellular and in vivo studies to assess the dynamic pattern of microglial activation and its relation to neuroinflammation and neuroregeneration (toxicity and repair) at various disease stages (early, late, under therapy) in AD, PD, HD, MS and ALS with the dual aim to develop and validate novel animal models and imaging biomarkers (PET, SPECT, MR and OI) capable to assess qualitatively and quantitatively regulation of microglial activity and function in vivo and to validate the outcome of known and newly developed neuroprotective strategies both in preclinical models and in patients. Thus the main scientific focus of the INMiND project is identification of molecular target/imaging biomarker combinations for activated microglia that can be used to develop and validate theranostics based on non-invasive in vivo imaging tools and this as early as possible in the disease stage, increasing the likelihood to positively influence the disease activity. Furthermore, INMiND is determined to sustain the project outcome by timely dissemination of generated knowledge and by training of a new generation of researchers through organisation of dedicated training activities related to neuroinflammation, neurodegeneration/-regeneration and imaging with special emphasis on translating basic mechanisms into clinical applications.
To achieve the project goals, several objectives are being pursued and embedded within a translational and reverse-translational strategy within 10 strongly interrelated scientific work packages (WPs) (Fig. 1). The main focus of the individual WPs is related to basic mechanisms of NIND regulation (WP1/2), development of imaging probes for NIND detection (WP3/4), validation of targets and imaging probes in animal models of NIND (WP5/6), applications in NIND humans (WP8/9), quantification of imaging biomarkers (WP7) and training of a new generation of cross-disciplinary scientists in the field of NIND (WP12). Beside the scientific WPs, 2 WPs deal with management, dissemination and integration issues (WP10/11) (Fig. 2). Overall, 7 scientific project objectives were defined at project beginning and tackled by several WPs in a concerted manner (Fig. 3).
The INMiND consortium is a unique interdisciplinary research consortium established by 28 complementary partners with leadership expertise in various fields (basic, translational, reverse-translational and clinical neuroscience and molecular neuroimaging; development of cellular and animal models, tracers and contrast agents; image validation, quantification and theranostics) including 6 SMEs, from 12 European countries and Australia (list of partners).

Project Results:
To reach the scientific objectives an important amount of work has been performed. To identify novel mechanisms of regulation and function of microglia under inflammatory stimuli, molecular targets, standardised procedures and protocols for isolation and in vitro and in vivo investigation of M1/M2 microglial activation types were defined (e.g. M1-LPS, M2-IL4), shared and successfully applied in various NIND models to characterise disease or evaluate pharmacological manipulations (WP1/2/5/6). Reporter systems sensitive for the conditional expression of imaging biosensors in specific cell types (M1 or M2 polarised cells) or conditions (protein oligomerisation, neurogenesis) have been developed and the generated M1 report mice validated in vivo (WP1/2/5/6). Novel robust NIND animal models (hP2X7, α-synuclein, LPS, IL4, IL13) have been generated and used for PET tracer development (WP3) or disease model characterisation (WP5/6). The interrelation between microglial activation and neuroregeneration (NR) has been characterised in vivo (WP2) and various studies investigated the role of sex hormones and the gender-specific differences in microglial activation, NI and NR (WP1/2). Novel radiotracers for NIND targets identified at the beginning of the project (TSPO and non-TSPO targets such as MMP, P2X7, CB2, H4, MAO-B) have been produced, optimised (WP3) and made available for human or animal studies (WP5/6/8). The new identified biological targets and lead compounds suitable for PET imaging of M2 microglia phenotypes have been further validated in vitro and in vivo for their biological, translational and radiopharmaceutical validity (WP1/2/3/5). For the four most promising targets (QPCT, CGRP, P2Y12 and P2Y14) several lead and first radiolabelled compounds have been synthesised and tested in rodent models (WP3). Highly sensitive micro- and nano-sized probes suitably designed for the visualisation of NI by MR and optical modalities have been designed, characterised, and optimised for enhanced imaging performance and validated by in vivo acute neuroinflammation models (WP4). Imaging studies with the various available imaging tools (PET, SPECT, MRI and OI) have been carried out in a range of preclinical and clinical NIND disease models and conditions to assess the dynamics of microglial activation and related NR and ND (WP5/6/8). NI imaging findings were correlated with histopathological findings and with imaging findings related to other disease-specific hallmarks (amyloidosis, astrogliosis, blood-brain barrier permeability, cell density, connectivity, etc). In these imaging studies a variety of PET tracers have been extensively evaluated and the performance of several tracers directly compared. Several neuroprotective and -regenerative strategies have been evaluated and PET, SPECT and/or MRI have been used as imaging readouts to monitor treatment response in animal models (WP1/2/5/6) and human studies (WP8). First patients have been enrolled in an image-guided RPCT to validate a novel protective strategy based on the use of TNFα inhibition that predictively will have a protective effect in MCI subjects (WP9). To allow uniform data analysis in clinical and preclinical studies, standardised procedures for quantitative analytical methods to assess the dynamics of microglial activation and tracer kinetic models for five different PET tracers were developed (WP5/6/7/8) and a European database of PK11195 data in healthy volunteers completed (WP7). Furthermore, high-level education within the field of INMiND-related research topics has been ensured within the consortium through 17 individual research residencies at partner institutions and outside the consortium through 27 dedicated training courses, which attracted 416 participants (WP12). Dissemination of INMiND-related foreground has been warranted by publication of 201 peer-reviewed papers and presentation of 305 lectures and 246 posters at 267 national and international conferences.

Potential Impact:
A large part of the project efforts are directed towards identification and development of alternative methods to assess dynamics of NI in relation to onset and progression of ND with non-invasive imaging techniques. Results of INMiND will shed novel light on the concerted molecular interactions and the genetic and hormonal contributions between pathological protein processing, microglia-mediated neurodestruction and neurorepair functions and define additional targets for the development of imaging biomarkers and therapeutics that will allow earlier and better diagnosis and treatment of patients with ND. To study basic pathophysiological mechanisms of microglial activation (M1 or M2) as well as the interplay between activated microglia and NPC and its consequences on neuroregeneration, specific experimental systems will be generated such as optimised microglia cell culture systems, transgenic reporter animals in which the expression of a multimodality reporter is controlled by M1 or M2 responses in activated microglia or LV-vector based reporter systems for monitoring of neurogenesis or protein oligomerisation. Non-invasive assessment of NI in vivo is currently based primarily on one target (TSPO) and one imaging biomarker ([11C]PK11195). Although [11C]PK11195 gives good imaging signals under severe neuroinflammatory conditions, it seems to be less useful to detect more subtle alterations. Moreover, lack of good performance of [11C]PK11195 in terms of specificity and signal-to-noise ratio and the presence of different affinity states of the binding site urges the development of new imaging ligands. In this respect will the INMiND project develop, implement and validate improved imaging biomarkers for NIND, not only directed to TSPO but also to other known (e.g. MMP, P2X7, CB2, H4, MAO-B) or newly identified complementary molecular target/imaging biomarker combinations and which can be detected by PET/SPECT/MRI and/or OI and used for early diagnosis and therapy evaluation, both preclinically and clinically. Also methods will be developed or optimised enabling quantification of imaging studies (e.g. image derived input functions, reference tissue models, supervised cluster analysis methods, partial volume correction methods). The final goal is that the developed imaging biomarkers enable in vivo assessment of the phenotypic profile of microglia (M1/M2) and differentiate specific disease stages with the extent and degree of associated neuronal and glial damage providing the possibility to direct therapeutic intervention. This knowledge will lead to an optimised and personalised patient care with image-guided patient selection at very early disease stages, where promising and innovative therapies still have the potential to preserve neuronal function and patient well-being. Moreover, the established imaging paradigms will be translatable to other diseases, where imaging biomarkers play a role in diagnosis and early assessment of therapy efficiency. Image-guided therapeutic strategies for NIND patients will have a great impact on disease course (delay of disease progression), quality of life (patient and family well-being) and informal and social care costs.
Work performed within INMiND is resulting from collaborative research efforts between several partners from academia and private enterprises. These concerted actions will lead not only to an efficient use of resources and know-how but also to a timely dissemination and exploitation of know-how and material (e.g. animal models, imaging probes, culture conditions), among INMiND partners as well as towards the scientific community and the general public. Last but not least will the INMiND educational programme efficiently support the creation of a new generation of highly trained researchers, increase competitiveness and support brain gain to Europe.

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