Characterizing neuroinflammation in human patients with temporal lobe epilepsy using [18F]FEPPA PET
Poster No:
414
Submission Type:
Abstract Submission
Authors:
Theodore Imhoff-Smith1, Alan McMillan1, Mariel Aparicio1, Brinda Sevak1, Rosario Ciliento1, Veena Nair1, Vivek Prabhakaran1, Nagesh Adluru1, Aaron Struck1
Institutions:
1University of Wisconsin-Madison, Madison, WI
First Author:
Co-Author(s):
Introduction:
Drug resistance in epilepsy is associated with increased mortality, poor quality of life, and cognitive, affective, and social disabilities. Epilepsy is also characterized by widespread neuroinflammation, a potential causative factor and consequence of seizures. Pathology from temporal lobe epilepsy (TLE) patients and mouse models of epilepsy have found elevated levels of interleukins, toll-like receptors, microglial/monocyte activation, and Tumor Necrosis Factors (TNFs), underscoring the inflammatory nature of the condition. Translocator Protein (TSPO) serves as a biomarker for neuroinflammation in humans and animals, predominantly reflecting microglial activation. [18F]FEPPA, a third generation TSPO radioligand, has demonstrated success in human positron emission tomography (PET) studies, offering favorable binding kinetics for effective imaging of neuroinflammation in humans. Despite its potential, application of FEPPA for understanding brain inflammation in humans, particularly in epilepsy, is in its early stages. This study employs [18F]FEPPA PET/MR to characterize neuroinflammation in TLE patients to better understand the interplay between seizures and neuroinflammation in humans.
Methods:
Clinical data, T1-weighted MR and FEPPA PET images were acquired from 15 patients (age=35+/-12.4, 10 male) and 12 controls (age=39.5+/-12.0, 6 male) on a GE HealthCare Signa simultaneous 3T PET/MR system. T1-weighted MR images were processed using FreeSurfer (v7) to skull-strip, register and derive anatomical parcellations of reconstructed PET images using the Destrieux atlas for region of interest (ROI) analysis of the PET data. Participants were classified as high, low, or mixed-affinity binders based on TSPO polymorphism (rs6971). Preliminary analysis excluded participants with a low allele and those missing clinical or imaging data, resulting in 10 patients (age=38.7+/-12.9, 6 high allele, 6 males) and 7 controls (age=33.3+/-8.3; 5 high allele, 5 males). FEPPA binding was quantified with standard uptake values (SUVs) for motion-corrected PET images reconstructed between 50-70 minutes post injection. Mean SUV was computed for each ROI and group differences were tested for significance using linear modeling via the lm package in R by regressing mean SUV on group for each allele type. ROI analyses were corrected for false discovery rate (FDR) using the Benjamini-Hochberg procedure.
Results:
As shown in Fig. 1, FEPPA uptake is greater in TLE patients compared to controls when grouped over both alleles (t(15)=2.45, p=.027) and within the high allele group (t(9)=2.75, p=.023). Group differences in the mixed allele group were not significant (t(4)=0.58, p=.595). Increased FEPPA SUV (p<.05, FDR corrected) was observed in TLE patients compared to controls across at least 25% of brain regions within all lobes of participants with the high allele (Fig. 2).
·Fig 1. Mean uptake in TLE patients compared to controls for each allele.
·Fig 2. Percent of regions in each lobe with significantly more uptake in epilepsy (p<.05 with FDR correction using Benjamini-Hochberg procedure).
Conclusions:
This study provides promising preliminary insights into neuroinflammation in human patients with epilepsy. Elevated FEPPA uptake across brain regions in humans with TLE aligns with the established link between epilepsy and heightened levels of interleukins, toll-like receptors, and microglial/monocyte activation in animal models and underscores the pervasive nature of neuroinflammation in the disorder. These results show promise for future analysis investigating relationships between FEPPA uptake, seizure occurrence, and other clinical variables, highlight the importance of targeting inflammation as a potential avenue for therapeutic interventions, and the potential of FEPPA as a sensitive neuroinflammatory biomarker for monitoring disease progression and treatment responses in humans with epilepsy.
Acknowledgements: We thank Heather Floerke for her contribution processing the blood samples.
Acknowledgements: We thank Heather Floerke for her contribution processing the blood samples.
Disorders of the Nervous System:
Neurodevelopmental/ Early Life (eg. ADHD, autism) 1
Modeling and Analysis Methods:
PET Modeling and Analysis
Novel Imaging Acquisition Methods:
PET 2
Keywords:
Acquisition
DISORDERS
Epilepsy
Glia
MRI
Neurological
Positron Emission Tomography (PET)
STRUCTURAL MRI
1|2Indicates the priority used for review
Provide references using author date format
Löscher, W., et al. (2020), 'Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options', Pharmacological Reviews, 72(3), 606-638.
Maroso, M., et al. (2010), 'Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures', Nature Medicine, 16(4), p. 413-9.
Rusjan PM, et al. (2011), 'Quantitation of translocator protein binding in human brain with the novel radioligand [18F]-FEPPA and positron emission tomography', Journal of Cerebral Blood Flow & Metabolism, 31(8), 1807-1816.
Vezzani, A., et al. (2011), 'The role of inflammation in epilepsy', Nature Reviews Neurology, 7(1), p. 31-40.