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.
First, 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.
We presented our work at 2 international congresses in Madrid and San Diego in 2022, and 3 more abstracts were accepted as oral and poster presentations in congresses during 2023, in Chicago, Barcelona and Montréal. 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. 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 4 seminars in Stockholm (Karolinska Institute), Madrid (Autonomous University of Madrid and Ramon y Cajal Institute), Peru (Universidad Tecnológica del Perú), and New York (Columbia University) where I also communicated our novel works on neuroimaging. Finally, we organized a symposium at the University of Barcelona for knowledge transfer and consolidating bridges between Toronto-Barcelona-Köln with relevant researchers in the movement disorders field.
