Nicotinic receptor abnormalities as a biomarker in idiopathic generalized epilepsy
- 197 Downloads
Mutations of cholinergic neuronal nicotinic receptors have been identified in the autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), associated with changes on PET images using [18F]-F-85380-A (F-A-85380), an α4β2 nicotinic receptor ligand. The aim of the present study was to evaluate potential changes in nicotinic receptor availability in other types of epilepsy.
We included 34 male participants, 12 patients with idiopathic generalized epilepsy (IGE), 10 with non-lesional diurnal focal epilepsy, and 12 age-matched healthy controls. All patients underwent PET/CT using F-A-85380 and [18F]-fluorodeoxyglucose (FDG), 3D T1 MRI and diffusion tensor imaging (DTI). F-A-85380 and FDG images were compared with the control group using a voxel-wise (SPM12) and a volumes of interest (VOI) analysis.
In the group of patients with IGE, the voxel-wise and VOI analyses showed a significant increase of F-A-85380 ratio index of binding potential (BPRI, corresponding to the receptor availability) in the anterior cingulate cortex (ACC), without structural changes on MRI. At an individual level, F-A-85380 BPRI increase in the ACC could distinguish IGE patients from controls and from patients with focal epilepsy with good accuracy.
We observed focal changes of density/availability of nicotinic receptors in IGE, namely an increase in the ACC. These data suggest that the modulation of α4β2 nicotinic receptors plays a role not only in ADNFLE, but also in other genetic epileptic syndromes such as IGE and could serve as a biomarker of epilepsy syndromes with a genetic background.
KeywordsNicotinic receptors Focal epilepsy Idiopathic generalized epilepsy PET F-A-85380
We would like to thank Antoine Depaulis (Grenoble Institut des Neurosciences, France), Michel Bottlaender (CEA, NeuroSpin, Gif / Yvette, France) and Frédéric Bois (Geneva University Hospitals, Geneva, Switzerland) for helpful comments, Claire Bridel (University Hospitals of Geneva) for her help in the recruitment of the individuals, and Marie-Louise Montandon for her work in MRI analyses. With contributions of the Clinical Research Center, Geneva University Hospitals and Faculty of Medicine, Geneva.
FP, MW, MS, OR, YS, VG and SH contributed to the conception and design of the study, VG, SH, GZ, RG, YS, FP and MW performed acquisition and analysis of data, FP, VG, MS, OR and SH drafted the manuscript.
The work was funded by the Swiss National Science Foundation (n° 320030_127608).
Compliance with ethical standards
Conflict of interest
All authors declare that they have no conflict of interest.
All procedures performed in this study involving human participants were conducted in accordance with the Swiss ethical standards and with the 1964 Helsinki declaration and its later amendments. The study protocol was approved by the Ethics Committee of the Geneva University Hospitals (CER 10-041) and by the Swiss agency for medications (Swissmedic: study n°2011DR1031). The study was recorded in ClinicalTrials.gov (n° NCT03268369).
Written informed consent was obtained from all participants.
- 1.Picard F, Scheffer I. Genetically determined focal epilepsies. In: Bureau M, Genton P, Dravet C, Delgado-Escueta AV, Tassinari CA, Thomas P, et al., editors. Epileptic syndromes in infancy, childhood and adolescence. 5th ed. Montrouge: John Libbey Eurotext; 2012. p. 349–61.Google Scholar
- 9.Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE commission on classification and terminology, 2005-2009. Epilepsia. 2010;51(4):676–85. https://doi.org/10.1111/j.1528-1167.2010.02522.x.CrossRefGoogle Scholar
- 16.Meyer PM, Strecker K, Kendziorra K, Becker G, Hesse S, Woelpl D, et al. Reduced alpha4beta2*-nicotinic acetylcholine receptor binding and its relationship to mild cognitive and depressive symptoms in Parkinson disease. Arch Gen Psychiatry. 2009;66(8):866–77. https://doi.org/10.1001/archgenpsychiatry.2009.106.CrossRefPubMedGoogle Scholar
- 17.Kendziorra K, Wolf H, Meyer PM, Barthel H, Hesse S, Becker GA, et al. Decreased cerebral alpha4beta2* nicotinic acetylcholine receptor availability in patients with mild cognitive impairment and Alzheimer’s disease assessed with positron emission tomography. Eur J Nucl Med Mol Imaging. 2011;38(3):515–25. https://doi.org/10.1007/s00259-010-1644-5.CrossRefPubMedGoogle Scholar
- 33.Bai X, Vestal M, Berman R, Negishi M, Spann M, Vega C, et al. Dynamic time course of typical childhood absence seizures: EEG, behavior, and functional magnetic resonance imaging. J Neurosci. 2010;30(17):5884–93. https://doi.org/10.1523/JNEUROSCI.5101-09.2010.CrossRefPubMedPubMedCentralGoogle Scholar
- 39.Paulus FM, Krach S, Blanke M, Roth C, Belke M, Sommer J, et al. Fronto-insula network activity explains emotional dysfunctions in juvenile myoclonic epilepsy: combined evidence from pupillometry and fMRI. Cortex. 2015;65:219–31. https://doi.org/10.1016/j.cortex.2015.01.018.CrossRefPubMedGoogle Scholar
- 43.Berdiev RK, Chepurnov SA, Veening JG, Chepurnova NE, van Luijtelaar G. The role of the nucleus basalis of Meynert and reticular thalamic nucleus in pathogenesis of genetically determined absence epilepsy in rats: a lesion study. Brain Res. 2007;1185:266–74. https://doi.org/10.1016/j.brainres.2007.09.010.CrossRefPubMedGoogle Scholar
- 46.Depaulis A, Charpier S. Pathophysiology of absence epilepsy: insights from genetic models. Neurosci Lett. 2017. https://doi.org/10.1016/j.neulet.2017.02.035.
- 48.Dickinson JA, Kew JN, Wonnacott S. Presynaptic alpha 7- and beta 2-containing nicotinic acetylcholine receptors modulate excitatory amino acid release from rat prefrontal cortex nerve terminals via distinct cellular mechanisms. Mol Pharmacol. 2008;74(2):348–59. https://doi.org/10.1124/mol.108.046623.CrossRefPubMedGoogle Scholar
- 52.Couey JJ, Meredith RM, Spijker S, Poorthuis RB, Smit AB, Brussaard AB, et al. Distributed network actions by nicotine increase the threshold for spike-timing-dependent plasticity in prefrontal cortex. Neuron. 2007;54(1):73–87. https://doi.org/10.1016/j.neuron.2007.03.006.CrossRefPubMedGoogle Scholar
- 53.Bekenstein U, Mishra N, Milikovsky DZ, Hanin G, Zelig D, Sheintuch L, et al. Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity. Proc Natl Acad Sci U S A. 2017;114(25):E4996–5005. https://doi.org/10.1073/pnas.1701201114.CrossRefPubMedPubMedCentralGoogle Scholar
- 61.Hosmer DW, Lemeshow S. Chapter 5. Assessing the fit of the model. Applied Logistic Regression, 2nd Ed. Wiley 2000.Google Scholar