Refining seizure foci localization: the potential of TSPO-PET

Abstract

Translocator protein positron emission tomography (TSPO-PET) is a novel imaging modality that leverages the high expression of TSPO in activated microglia and other cells within seizure foci. It has been increasingly applied in the preoperative evaluation of drug-resistant epilepsy (DRE) to aid in the localization of these foci. With advances in tracer development, TSPO-PET has achieved higher signal-to-noise ratios and broader clinical utility. Clinical studies indicate that TSPO-PET yields significantly higher positive detection rates for seizure foci compared to magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. This review summarizes recent progress in TSPO-PET radiotracer technology, its mechanism of action, and its clinical applications for managing DRE.

Keywords: Drug-resistant epilepsy; Neuroinflammation; Positron emission tomography; Seizure foci; Translocator protein.

Fig. 1

External stimuli like seizures can activate intracellular signaling cascades, leading to the overexpression of the TSPO in microglia and astrocytes within seizure foci. Upon stimulation, the PKC$ϵ$ pathway is initiated, sequentially activating Raf1, MEK1/2, and ERK1/2. The signaling cascade reaches the nucleus, where transcription factors such as STAT3 and c-Jun combine as AP-1 and modulate gene expression. In mice, the availability of AP-1 binding sites promotes the upregulation of TSPO, enhancing inflammatory responses and mitochondrial dysfunction. However, in humans, the absence of AP-1 binding sites leads to normal TSPO levels under epileptic conditions

Fig. 2

Comparison of TSPO-PET tracers: pharmacokinetics, BBB permeability, binding characteristics, and SNP effects. a Blood components and nonspecific binding of TSPO tracers. First-generation (blue) shows high nonspecific binding; second- (orange) and third-generation (green) tracers show minimal peripheral binding. b BBB permeability. First-generation tracers show poor penetration, while second- and third-generation tracers cross the BBB efficiently for better brain uptake and contrast. c Radiotracer decay. First-generation tracers decay quickly, while second- and third-generation tracers enable longer imaging. d TSPO-PET images comparing [$_{}^{11}$C]PK11195 and [$_{}^{11}$C]PBR28, showing higher signal-to-noise and contrast with second-generation tracers. Permission was granted by Parente A, et al. (©SNMMI [80]) to reuse this figure. (e) rs6971 SNP effects. Second-generation tracers (orange) show reduced binding in LABs; third-generation (green) maintain binding; first-generation (blue) are unaffected but limited by other issues

Fig. 3

TSPO-PET demonstrates superior seizure focus localization compared to MRI and FDG-PET in various clinical scenarios. a, b In a patient with normal MRI findings (a), TSPO-PET (b) reveals a focal area of increased uptake (black circle), indicating an epileptogenic region that was undetectable on structural imaging. c-d In another case with normal FDG-PET (c), TSPO-PET (d) identifies a previously unrecognized hyperinflammatory focus (black circle), highlighting its added diagnostic value when metabolic imaging is inconclusive. e, f In a patient with FDG-PET hypometabolism (e), TSPO-PET (f) shows more restricted and well-defined uptake (black circle), providing higher spatial precision for surgical planning. Permission was granted by Qiao Z et al. (©Wiley [81] license No. [6015940098201]) to reuse this figure

Fig. 4

Schematic illustration of favorable and unfavorable factors influencing TSPO-PET imaging results. Key factors affecting TSPO-PET results include the time interval between the last seizure and the TSPO-PET scan—earlier imaging (within approximately 2 weeks) after a seizure is associated with higher TSPO tracer uptake; the severity of epilepsy—patients with higher GASE scores tend to show stronger TSPO-PET signals; the seizure type—patients with TLE tend to show more localized TSPO-PET signals than those with ETLE