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Periodic Report Summary 2 - MULTISYN (Multimodal Imaging of rare Synucleinopathies)

Project Context and Objectives:
Neurodegenerative diseases, such as Alzheimer’s disease (AD) or Parkinson’s disease (PD) are progressive, devastating and incurable neurologic conditions. The aggregation of disease-specific abnormally folded proteins, such as the A-beta protein in AD or α-synuclein (αSYN) in PD, and probably their spreading from cell to cell throughout the brain, appears to be the central driver of pathogenesis. The removal of these aggregates holds considerable promise as a therapeutic strategy. However, the relationship between protein misfolding and aggregation on the one hand, and neuronal dysfunction and cell death, on the other hand, is far from being well understood, particularly in the common sporadic forms of these disorders. As a consequence, rare genetically defined forms of neurodegenerative disorders are now generally considered to offer substantial advantages for drug development such as a clear cause-effect-relationship and the possibility of diagnosis at an early stage of the disease process when it is still possible to modify its course.
Non-invasive imaging methods such as PET and MRI can be valuable tools to aid diagnosis of neurodegenerative diseases, provide input to differential diagnosis and follow disease progression or therapeutic effects of disease modifying treatments. However, for many important neurodegenerative diseases including the synucleinopathies, tauopathies, and TDP-43 proteopathies, specific PET tracers for the underlying cellular pathology, which would allow tracking the disease burden are still lacking. Moreover, there has been no systematic work performed to link neuronal function as detected by fMRI with molecular information as provided by PET-imaging of aggregates in these diseases. Novel PET/MR imaging systems which could fill this knowledge gap for rodents and humans are available but require the establishment and validation of sensitive and aggregation specific tracers as well as of disease-specific imaging protocols and data analysis tools.
From these considerations it becomes evident, that there is an urgent need
(i) to develop novel and to re-evaluate existing PET-tracers that allow to track aggregated proteins and to develop multimodal imaging protocols to link protein aggregation pathology to functional read-outs on the systems level in animal models and in the corresponding human patient populations with rare, but well characterized model diseases, such as genetic proteopathies,
(ii) to validate these tracers in suitable animal models and to test their value as markers to monitor progression in disease-modifying treatment studies, and finally
(iii) to use these tracers to define the distribution and evolution of protein-aggregation pathology in human patients and to provide proof-of-concept that multimodal imaging protocols are suitable for monitoring disease-modifying individualized treatments.
In order to overcome the critical road-blocks described above, we have assembled an interdisciplinary consortium, consisting of world-leading experts in structural biology and ligand development, multimodal neuroimaging, animal models and clinical trials. We aim to

1. Establish a multimodal imaging workflow based on specific PET tracers and embracing structural and functional MRI methods to yield a tool that sensitively and specifically detects αSYN pathology and associated changes
2. Test this multimodal, molecular neuroimaging methodology in animal models with regard to its potential for diagnosis, monitoring the natural disease course and response to therapy, as well as guide and optimize therapeutic interventions.
3. Translate the workflow including the therapeutic modality (i.e. immunotherapy with PD01A, NCT01568099) to the clinical setting.

Project Results:
Aim 1 (WP1):
Development of labelling strategies for novel PET tracer
- Approach for 11C- anle253b, 18F-sery363b, 11C-sery392b and 11C-sery512a developed
- Compounds anle138b, anle2F4CP, sery383, anle1479, and sery512a were tritiated and used for autoradiography and other binding studies.

Characterization of binding affinity and specificity of PET compounds in vitro
- Successful quantification of binding affinities for all tritiated compounds
- Demonstration of specific binding of 11C-PIB to αSYN aggregates and competition experiments revealed highest blocking for PIB, anle2F4CP, anle138b and sery383.
- Development of a software tool for PET to histology coregistration for AR

PET tracer evaluation
- Set up and evaluation of a blood sampling device to accurately measure tracer and metabolite activity in plasma
- Demonstration of high binding of 11C-anle253b to αSYN fibrils in comparison to monomers and oligomers.
- Using human brain tissue, autoradiography studies revealed binding of all tritiated anle and sery tracers to Abeta in AD brain
- 3H-anle2F4CP tracer binds diffusely to the frontal cortex of LBD patients more than to control brain tissue.

Set-up of dedicated PET/fMRI scan protocols for 18F-FDG and 11C-raclopride in rats

Development of a dedicated PMOD software module
- Inclusion of parametric mapping into PNEURO for synergistic PET/MR analysis
- Extension of PNEURO from human to animal brains.
- Addition of a perfusion mapping plug-in for ASL MRI data and diffusion mapping and tensor calculation plug-in for DTI MRI data.
- R scripts for the statistical analysis of multiparametric outcome data in longitudinal studies.
- Extension to integrated analysis of the multi-modal image data

Aim 2 (WP2):
- Use of PET imaging to validate a novel AAV-aSYN pig model.
- 11C-Sery392b tracer showed increased uptake in the striatum and ventral midbrain of pig models on the side of injection of AAV-aSYN.
- Evidence that AAV-mediated rat model suitable for testing a various PET tracer and imaging protocols
- AAV-αSYN rat model: positive correlation between 11C-PIB binding and αSYN load as well as dopaminergic cell loss, measured with 11C-methylphenidate and postsynaptic D2 receptor expression changes, measured with 11C-raclopride.
- AAV-αSYN rat model: Preliminary MR spectroscopy data show reductions of glutamate concentrations
- A30P mouse model: 11C-sery512a and 11C-PIB PET showed good uptake kinetics, highest binding in the brain stem and was higher in 73 weeks old tg mice compared to 20 weeks controls.
- MSA PLP-ASYN tg mouse model: demonstrates an increased ASYN burden throughout its lifespan, ASYN levels specifically analysed
- CMA induction via LAMP2A up-regulation represents an effective strategy to mitigate established ASYN pathology in BAC-hu-ASYN rats.
- In vitro and in vivo data support specific binding of 11C-PIB to αSYN fibrils and aggregates
- PD01 and PD03 AFFITOPEs are immunogenic in Sprague Dawley’s rats, induced antibodies are able to cross-react with the αSYN original epitope and the recombinant human αSYN protein.

Aim 3 (WP3):
- Multimodal PET/MRI protocols in humans have been established and tested in a pilot study in patients with MSA; GBA-PD and controls
- A53T-PD cohort characterized: longitudinal clinical assessments showed prominent motor decline and deterioration of autonomic and cognitive function during the study period, providing baseline values to inform on future clinical trials.
- MSA cohort characterized: The midbrain and putaminal volume as well as the cerebellar gray matter compartment were identified as the most significant brain regions to construct a prediction model for the diagnosis of MSA.
- GBA cohort characterized: Natural history of PD caused by GBA-mutations (GBA-PD) focusing particularly on non-motor symptoms established, as a basis for designing clinical interventional trials and power calculations.

Potential Impact:
Upon completion of WP1 we aim to have established and validated labelled tracers, PET/MR imaging workflows and data analysis tools available to utilize the full potential of temporally correlated functional, molecular and morphological in vivo data to monitor progression of pathology in αSYN aggregation disorders. These tools and workflows will be available for preclinical imaging studies in animals as well as in clinical studies. In addition, approval for clinical studies will be obtained.

WP2 is going to establish the experimental basis and present the proof-of-concept for simultaneous PET/MRI imaging as a powerful tool for assessing disease related changes in animal models and provide proof of concept for the use of this method to monitor disease modifying treatments for rare forms of synucleinopathies. At the completion of the work, we will not only be leading the field internationally in how such imaging biomarkers can be implemented to benefit disease staging and define therapeutic benefits in animal models of a specific class of neurodegenerative diseases but will also have established the data set required to take the next step into clinical testing.

In WP3, we expect to fully characterize the signal distribution which, based on our results in animal models, most likely reflects the distribution of the αSYN aggregates, as imaged by using specific tracers such as anle138-PET-compounds (such as sery363a and sery392b) and PIB, as it evolves over time in the brain of human patients with MSA and inherited PD due to αSYN mutations. Secondly, we expect to define the relationship between αSYN deposition and functional connectivity of the brain and the function of the dopaminergic synapse, as visualized by PET/fMRI co-registration cross-sectionally.

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