SV2A PET Imaging Is a Noninvasive Marker for the Detection of Spinal Damage in Experimental Models of Spinal Cord Injury

Abstract

Traumatic spinal cord injury (SCI) is a neurological condition characterized by long-term motor and sensory neurological deficits as a consequence of an external physical impact damaging the spinal cord. Anatomical magnetic resonance imaging (MRI) is considered the gold-standard diagnostic tool to obtain structural information for the prognosis of acute SCI, however, it lacks functional objective information to assess SCI progression and recovery. In this study, we explored the use of synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging to detect spinal cord lesions non-invasively following SCI.METHODS: Mice (n=7) and rats (n=8) subjected to unilateral moderate cervical (C5) contusion were euthanized 1-week post-SCI for histological and autoradiographic ( 3 H-UCB-J) investigation of SV2A levels. Longitudinal 11 C-UCB-J PET/computed tomography (CT) imaging was performed in sham (n=7) and SCI rats (n=8) 1 week and 6 weeks post-SCI. Animals also underwent an 18 F-FDG PET scan during the latter time point. Post-mortem tissue SV2A analysis to corroborate in vivo PET findings was performed 6 weeks post-SCI. RESULTS:A significant SV2A loss (ranging from -70.3% to -87.3%; P<0.0001) was measured at the epicenter of the impact in vitro in both mouse and rat contusion SCI models. Longitudinal 11 C-UCB-J PET imaging detected SV2A loss in SCI rats (-49.0±8.1% at 1 week and -52.0±12.9% at 6 weeks post-SCI), with no change observed in sham rats. In contrast, 18 F-FDG PET imaging measured only subtle hypometabolism (-17.6±14.7%). Finally, post-mortem 3 H-UCB-J autoradiography correlated with the in vivo SV2A PET findings (r=0.92, P<0.0001).CONCLUSION: 11 C-UCB-J PET/CT imaging is a non-invasive marker for SV2A loss following SCI. Collectively, these findings indicate SV2A PET may provide an objective measure of SCI, and thus a valuable tool to evaluate novel therapeutics. Clinical assessment of SCI with SV2A PET imaging is highly recommended.

Validation, kinetic modeling, and test-retest reproducibility of [18F]SynVesT-1 for PET imaging of synaptic vesicle glycoprotein 2A in mice

“…8,[11][12][13][14] Given the instrumental role of preclinical models in understanding neuropsychiatric and neurodegenerative disorders in parallel to the broad spectrum of diseases characterized by synaptic dysfunction, we previously described the application of [ 11 C]UCB-J in mice 15 and the utility of [ 11 C]UCB-J PET imaging in preclinical models to significantly advance our understanding of the pathophysiology and diagnosis of neurological disorders, including Huntington's disease, 16 obsessivecompulsive disorder, 17 and spinal cord injury. 18 Despite the excellent preclinical and clinical properties as a radioligand, applicability of [ 11 C]UCB-J is limited to centers with an on-site cyclotron due to the short half-life of the C-11 radioisotope (20.4 min). In order to overcome this constraint, recent efforts have focused on the generation of a UCB-J analogue ligand incorporating the F-18 radioisotope, thus offering a longer half-life (109.8 min), translating into high research throughput and clinical utility at the majority of PET centers without a cyclotron.…”

“…Given the instrumental role of preclinical models in understanding neuropsychiatric and neurodegenerative disorders in parallel to the broad spectrum of diseases characterized by synaptic dysfunction, we previously described the application of [ 11 C]UCB-J in mice 15 and the utility of [ 11 C]UCB-J PET imaging in preclinical models to significantly advance our understanding of the pathophysiology and diagnosis of neurological disorders, including Huntington’s disease, 16 obsessive-compulsive disorder, 17 and spinal cord injury. 18 …”

Identification of pre-synaptic density networks using SV2A PET imaging and ICA in healthy and diseased mice

“…In the near future, it will be interesting to expand this approach to cross-species (e.g. people with HD given the reported loss of SV2A (Delva et al, 2022), as well as to other disorders known to affect SV2A, both preclinically (Bertoglio et al, 2021; Bertoglio et al, 2022a; Glorie et al, 2020) and clinically (Chen et al, 2018; Finnema et al, 2020; Holmes et al, 2019; Matuskey et al, 2020).…”

“…In addition to human application, [ 11 C]UCB-J displayed excellent imaging characteristics in rodents and non-human primates (Bertoglio et al, 2020;Nabulsi et al, 2016;Thomsen et al, 2021). Thus, [ 11 C]UCB-J PET imaging can be applied in a preclinical setting to model neurological and neuropsychiatric disorders as demonstrated by recent studies by our and other groups (Bertoglio et al, 2022a;Bertoglio et al, 2022b;Glorie et al, 2020;Toyonaga et al, 2019) Given the brain-wide distribution of SV2A, regional analysis of SV2A PET data may be limiting the amount of information that can be obtained. In this context, data-driven approaches such as independent component analysis (ICA), a blind source separation technique, can separate the brain signal into distinct components, here defined as presynaptic density networks (pSDNs), without having any knowledge beforehand about the source signals (Bell and Sejnowski, 1995).…”

“…In addition to human application, [ 11 C]UCB-J displayed excellent imaging characteristics in rodents and non-human primates (Bertoglio et al, 2020; Nabulsi et al, 2016; Thomsen et al, 2021). Thus, [ 11 C]UCB-J PET imaging can be applied in a preclinical setting to model neurological and neuropsychiatric disorders as demonstrated by recent studies by our and other groups (Bertoglio et al, 2022a; Bertoglio et al, 2022b; Glorie et al, 2020; Toyonaga et al, 2019)…”