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Multimodal imaging in parkinsonisms: from the molecular synaptic pruning to the whole-brain connectomics

Periodic Reporting for period 1 - SYNPARK (Multimodal imaging in parkinsonisms: from the molecular synaptic pruning to the whole-brain connectomics)

Reporting period: 2020-09-01 to 2022-08-31

Parkinsonism is the 2nd most prevalent neurodegenerative syndrome, global estimates in 2019 showed over 8.5 million people were diagnosed with Parkinson’s disease (PD) according to WHO, and this number is expected to grow as the world population ages. According to the European Parliament, its economic impact is estimated at 13.9 billion € per year. About 80% of the diagnosed patients have a classical form of idiopathic PD whereas the rest present some form of atypical parkinsonism (AP). Differential diagnosis between AP and PD poses significant challenges for clinicians as clinical manifestations can overlap and there are no gold standard biomarkers. As disease-modifying therapies are becoming available, an accurate diagnosis is essential because in AP neuronal degeneration is generally more rapid and widespread, symptomatic therapy less effective and therefore, there is a greater caregiver burden and a major economic impact. The overarching aim of the SYNPARK project is to investigate the potential discriminative power of multimodal imaging markers in improving parkinsonism diagnostic accuracy. To address such a complex question, we proposed the study of the most cutting-edge Positron Emission Tomography (PET) molecular imaging techniques in combination with Magnetic Resonance Imaging (MRI) modalities to provide a better insight into parkinsonism pathology.
During the outgoing phase at the Centre for Addiction and Mental Health (CAMH), Toronto, I explored the specific binding and kinetic properties of the newly developed [18F]SynVesT-1 tracer as an indirect measure of quantifying synaptic density loss in parkinsonian patients. I also worked with other PET and MRI modalities to investigate the protein deposition, neurochemical abnormalities, brain atrophy, and functional disruptions underlying the degenerative process of PD and study its clinical manifestations heterogeneity.
The synaptic vesicle glycoprotein 2A (SV2A) is located in the brain's presynaptic vesicle membrane of synapses. SV2A PET can provide a quantitative measure of synaptic density in the in vivo human brain and serve as an indirect measure of synaptic density loss within the neurodegenerative process of PD and AP. To date, the [11C]UCB-J radioligand has been used to investigate synaptic density loss in PD patients. However, 18F-labeled tracers offer a longer half-life than the carbon-labelled tracer and in 2021, the SV2A radioligand [18F]SynVesT-1 (formerly named [18F]SDM-8) was tested for the first time in healthy controls.
During the first reporting period of this action (September 2020-August 2022), I received PET training and conducted preprocessing of dynamic PET, parametric mapping, kinetic modelling, and assessed specific binding of cutting-edge PET radioligands, i.e. the [18F]SynVesT-1. I also collaborated with colleagues at CAMH in the investigation of molecular systems and protein deposition in PD patients: (1) presynaptic dopaminergic integrity through vesicular monoamine transporter 2 (VMAT2) measurements with the [11C]DTBZ; (2) beta-amyloid density by means of [18F]florbetaben in the PPMI multicentre cohort; (3) neuroinflammatory processes through activated microglia by targeting the translocator protein (TSPO) using [18F]FEPPA; and (4) quantification of tau neurofibrillary tangles spreading in the brain of PD with dementia, PSP and corticobasal degeneration with a second generation tracer, the [18F]MK6240.
We investigated the in vivo binding properties of the [18F]SynVesT-1 tracer for the quantification of synaptic density loss in PD and Multiple System Atrophy (MSA) patients, as well as the binding of an MSA post-mortem brain. PET scans were acquired on a GE Discovery MI PET-CT. The radiotracer was injected via bolus injection (average of 5 mCi), and emission data were acquired for 120 min with arterial blood collection. A Simplified Reference Tissue Model 2 (SRTM2) to compute BPND values with the Centrum Semiovale as reference region was applied. Briefly, we computed the whole-brain BPND maps for PD patients which displayed a similar distribution of synaptic density in cortical areas in comparison with age-matched healthy controls, but lower density was observed in subcortical areas, in particular in the striatum. Regarding the MSA patients’ BPND map, a lateralized rightwards density loss was found with respect to the left hemisphere in cortical areas as well as a significant striatal loss with respect to both PD patients and healthy controls.
The [18F](R)-SDM8 binding was assessed in the striatum and occipital lobe of an MSA patient. Sections were sliced at 10 µm and stored at -80°C. Slides were thawed and dried at room temperature for at least 30 minutes. Tissue was incubated for 1h with [18F](R)-SDM8 (2nM and 12,400 mCi/µmole) or with 200µM levetiracetam. The post-mortem binding in sections of the striatum and occipital lobe of the postmortem brain of an MSA patient with the [18F](R)-SDM8 tracer displayed good specific binding distribution with respect to the levetiracetam blocking study. In sum, we conducted the first study with [18F]SynVesT-1 which displayed good binding distribution properties in parkinsonism patients. Hence, the use of this tracer is a promising tool for the investigation of synaptic loss in the striatum and to describe patterns of cortical synaptic depletion.
Several Dissemination and Communication activities were conducted during this period. Specifically, I have 2 accepted abstracts in international congresses celebrated in September and November 2022 as the first author, and 10 more published abstracts as co-author. I also participated in 2 communication activities in Toronto: (1) for researchers at CAMH and Krembil Institute, and (2) for a general audience in local TV news. Due to the COVID-19 restrictions, I also participated in online communication activities in Catalonia, Europe for high school and elementary schools: (1) Science is Wonderful, and (2) a Window to the Brain initiative from the Institute of Neuroscience at Universitat de Barcelona (UBNEURO). I have been invited speaker at 3 seminars in Stockholm (Karolinska Institute), Madrid (Autonomous University of Madrid and Ramon y Cajal Institute) and Peru (Universidad Tecnológica del Perú) where I also communicated our novel works on neuroimaging towards the understanding of PD pathology.
First, our novel findings on the use of the [18F]SynVesT-1 tracer in parkinsonian patients will facilitate a broader investigation of in vivo synaptic density loss than carbon-labelled tracers that have a smaller half-life. Second, non-invasive approaches without invasive arterial sampling (i.e. Simplified Reference Tissue Model 2 to compute BPND parametric maps) and the implementation of shorter scan time protocols will open the window in recruiting patients with all degrees of disease severity in many neurological and psychiatric conditions. Our work is the first in the literature to study different diagnostic entities within movement disorders.
Ultimately, the SYNPARK results do and will represent a significant step towards the validation of a new generation of imaging biomarkers in neurodegenerative processes to drive a revolution in personalized medicine and disease-modifying therapies. Thus, will reduce future medical expenses due to misleading diagnoses of treatment-resistant AP forms.

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