Abstract
Purpose
The loss of synaptic vesicle glycoprotein 2A (SV2A) is well established as the major correlate of epileptogenesis in focal cortical dysplasia type II (FCD II), but this has not been directly tested in vivo. In this positron emission tomography (PET) study with the new tracer 18F-SynVesT-1, we evaluated SV2A abnormalities in patients with FCD II and compared the pattern to 18F-fluorodeoxyglucose (18F-FDG).
Methods
Sixteen patients with proven FCD II and 16 healthy controls were recruited. All FCD II patients underwent magnetic resonance imaging (MRI) and static PET imaging with both 18F-SynVesT-1 and 18F-FDG, while the controls underwent MRI and PET with only 18F-SynVesT-1. Visual assessment of PET images was undertaken. The standardized uptake values (SUVs) of 18F-SynVesT-1 were computed for regions of interest (ROIs), along with SUV ratio (SUVr) between ROI and centrum semiovale (white matter). Asymmetry indices (AIs) were analyzed between the lesion and the contralateral hemisphere for intersubject comparisons.
Results
Lesions in the brains of FCD II patients had significantly reduced 18F-SynVesT-1 uptake compared with contralateral regions, and brains of the controls. 18F-SynVesT-1 PET indicated low lesion uptake in 14 patients (87.5%), corresponding to hypometabolism detected by 18F-FDG PET, with higher accuracy for lesion localization than MRI (43.8%) (P < 0.05). AI analyses demonstrated that in the lesions, SUVr for each of the radiotracers were not significantly different (P > 0.05), and 18F-SynVesT-1 SUVr correlated with that of 18F-FDG across subjects (R2 = 0.41, P = 0.008). Subsequent visual ratings indicated that 18F-SynVesT-1 uptake had a more restricted pattern of reduction than 18F-FDG uptake in FCD II lesions (P < 0.05).
Conclusion
SV2A PET with 18F-SynVesT-1 shows a higher accuracy for the localization of FCD II lesions than MRI and a more restricted pattern of abnormality than 18F-FDG PET.
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Introduction
Focal cortical dysplasia type II (FCD II) constitutes the most common cause of seizures in patients who undergo surgery before the age of 18 years [1]. Epilepsy in FCD II is commonly pharmacoresistant and thus particularly challenging for antiepileptic treatment [2]. Surgical resection of FCD II lesions may prevent seizures and improve quality of life [3]. It has been well established that the main predictor of favorable surgical outcomes is the complete removal of the dysplastic cortex.
FCD II is predominantly located in extratemporal areas, in particular the eloquent cortex [3]. Magnetic resonance imaging (MRI) features in FCD II have been widely described [4], but so-called negative MRI has been reported in 17–34% of patients and is associated with poor surgical outcomes [5]. Positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose (18F-FDG) has significantly improved the positive detection rate of lesions. However, maximal hypometabolic areas correspond to both the lesion and seizure onset zone [6]. The accuracy of 18F-FDG PET in identifying FCD II is limited by hypometabolism frequently extending beyond the lesion. Therefore, for FCD II patients, PET imaging with additional radioligands that can be used to guide more accurate demarcation of the lesion would be of great clinical value.
Observations from a rat model of epilepsy and dysplastic cortical tissue suggested that the loss of synaptic vesicle glycoprotein 2A (SV2A) may lead to alterations in neurotransmission [7]. SV2A loss can cause impairments in γ-aminobutyric acid (GABA)ergic function [8,9,10]. 11C-UCB-J, a specific radioligand for SV2A, has been used in the investigation of several neuropsychiatric diseases [10,11,12,13]. Compared to 11C-UCB-J, the newly reported SV2A radioligand 18F-SynVesT-1 has a longer half-life and superior signal-to-noise ratio [14, 15]. In a preliminary study using static 18F-SynVesT-1 PET, we demonstrated lower SV2A levels in the epileptogenic zone (EZ) of patients with FCD II [16]. In the present study, we included more FCD II patients with neuropathology data and controls. The FCD II patients were also evaluated with 18F-FDG PET and high-resolution MRI to allow for direct comparisons.
Materials and methods
Participants
Sixteen FCD II patients and 16 controls were included in the present study. Localization of the EZ was determined by at least 2 experienced epileptologists based on all available clinical, video-electroencephalographic (EEG), interictal EEG, neuroimaging, and invasive stereo-EEG (SEEG) monitoring data if indicated. Sixteen consecutive patients underwent surgery for intractable epilepsy and histologically proven FCD II (FCD type II includes two subgroups based on the absence (IIa) or presence (IIb) of balloon cells) [17]. The exclusion criteria included any current or past clinically significant medical or neurological illness (other than FCD) that could have affected the study outcome. Some antiepileptic drugs (AEDs) are known to decrease cerebral blood flow and metabolism [18, 19], and levetiracetam and brivaracetam bind to SV2A [20, 21]. Patients were excluded if they were taking levetiracetam or brivaracetam. Those who could discontinue AED were instructed to withhold their medication so that their last dose was at least 24 h before the scheduled 18F-SynVesT-1 injection time. Other patients who could not discontinue AED administration because of seizures that were too frequent were excluded from the study. All patients were closely monitored by a neurologist during MRI and PET imaging, and no clinical seizures were noted.
The study protocol was approved by the Human Investigation Committee and Radiation Safety Committee at ** (SPM), could not be conducted. As a result, we performed only a relatively subjective visual assessment and semiquantitative analysis/comparison between the child patient group and young adult control group. Further analysis will be conducted in future in-depth studies as we continue our investigation in this patient population.
Conclusions
To the best of our knowledge, this is the first in vivo study to investigate SV2A in the lesions of living people with FCD II by PET imaging with the radioligand 18F-SynVesT-1. 18F-SynVesT-1 PET demonstrated a higher accuracy than MRI for the localization of FCD II lesions, with a more restricted pattern of SV2A abnormality than that of hypometabolism detected by 18F-FDG PET. In conclusion, SV2A PET imaging may provide a more specific localization of lesions in FCD II, and in presurgical evaluation and planning, it can serve as a complementary measure of the epileptogenic substrate in addition to the established clinical assessments.
Data availability
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
Code availability
Not applicable.
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Acknowledgements
The authors extend their deepest appreciation to the research participants and their families.
Funding
This study was supported by the National Natural Science Foundation of China (Grant Nos. 81801740 and 91859207) and the National Science Foundation of Hunan Province (Grant No. 2020JJ5922).
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All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Yongxiang Tang, Jie Yu, Ming Zhou, Jian Li, Tingting Long, Yulai Li, Li Feng, Dengming Chen, and Zhiquan Yang. The first draft of the manuscript was written by Yongxiang Tang and Jie Yu. Yiyun Huang provided the prodrug and synthesis method of 18F-SynVesT-1, and Yiyun Huang and Shuo Hu revised the work critically for important intellectual content. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Approval was obtained from the ethics committee of the Ethical Commission of Medical Research Involving Human Subjects at the Region of **angya Hospital, Central South University, China. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.
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Yongxiang Tang and Jie Yu are contributed equally to this work as co-first authors
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Tang, Y., Yu, J., Zhou, M. et al. Cortical abnormalities of synaptic vesicle protein 2A in focal cortical dysplasia type II identified in vivo with 18F-SynVesT-1 positron emission tomography imaging. Eur J Nucl Med Mol Imaging 49, 3482–3491 (2022). https://doi.org/10.1007/s00259-021-05665-w
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DOI: https://doi.org/10.1007/s00259-021-05665-w