Brain Advance Access originally published online on June 30, 2006
Brain 2006 129(8):2047-2060; doi:10.1093/brain/awl156
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Alteration of the in vivo nicotinic receptor density in ADNFLE patients: a PET study
1 Department of Neurology, University Hospital and Medical School of Geneva Switzerland 2 CEA, Service Hospitalier Frédéric Joliot, DRM/DSV Orsay 3 CEA, Département d'Ingénierie et d'Etudes des Protéines Saclay, France 4 St Olav's Hospital, Trondheim University Hospital Trondheim Norway 5 Royal Hospital for Sick Children, Yorkhill Glasgow, UK 6 University Magna Graecia, Catanzaro Italy 7 University of Medical Sciences Poznan, Poland 8 Department of Neurology, University of Essen Essen, Germany
Correspondence to: Dr Fabienne Picard, Department of Neurology, University Hospital of Geneva, 24 rue Micheli-du-Crest, 1211 Geneva 14, Switzerland E-mail: Fabienne.Picard1{at}hcuge.ch
Nicotinic acetylcholine receptors (nAChRs) are involved in a familial form of frontal lobe epilepsy, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In several ADNFLE families, mutations were identified in the nAChR 
4 or ß2 subunit, which together compose the main cerebral nAChR. Electrophysiological assessment using in vitro expression systems indicated a gain of function of the mutant receptors. However the precise mechanisms by which they contribute to the pathogenesis of a focal epilepsy remain obscure, especially since 4ß2 nAChRs are known to be widely distributed within the entire brain. PET study using [18F]-F-A-85380, a high affinity agonist at the 4ß2 nAChRs, allows the determination of the regional distribution and density of the nAChRs in healthy volunteers and in ADNFLE patients, thus offering a unique opportunity to investigate some in vivo consequences of the molecular defect. We have assessed nAChR distribution in eight non-smoking ADNFLE patients (from five families) bearing an identified mutation in nAChRs and in seven age-matched non-smoking healthy volunteers using PET and [18F]-F-A-85380. Parametric images of volume of distribution (Vd) were generated as the ratio of tissue to plasma radioactivities. The images showed a clear difference in the pattern of the nAChR density in the brains of the patients compared to the healthy volunteers. Vd values revealed a significant increase (between 12 and 21%, P < 0.05) in the ADNFLE patients in the mesencephalon, the pons and the cerebellum when compared to control subjects. Statistical parametric mapping (SPM) was then used to better analyse subtle regional differences. This analysis confirmed clear regional differences between patients and controls: patients had increased nAChR density in the epithalamus, ventral mesencephalon and cerebellum, but decreased nAChR density in the right dorsolateral prefrontal region. In five patients who underwent an additional [18F]-fluorodeoxyglucose (FDG) PET experiment, hypometabolism was observed in the neighbouring area of the right orbitofrontal cortex. The demonstration of a regional nAChR density decrease in the prefrontal cortex, despite the known distribution of these receptors throughout the cerebral cortex, is consistent with a focal epilepsy involving the frontal lobe. We also propose that the nAChR density increase in mesencephalon is involved in the pathophysiology of ADNFLE through the role of brainstem ascending cholinergic systems in arousal.
Key Words: ADNFLE; genetics; nicotinic receptor; PET; fluoro-A-85380
Abbreviations:
ACh, acetylcholine; ADNFLE, autosomal dominant nocturnal frontal lobe epilepsy; CHRNA4, gene coding for the neuronal nicotinic acetylcholine receptor 4 subunit; CHRNB2, gene coding for the neuronal nicotinic acetylcholine receptor ß2 subunit; F-A-85380, 2-fluoro-A-85380; FDG, fluorodeoxyglucose; IPN, interpeduncular nucleus; LDT, laterodorsal tegmental nucleus; nAChR, nicotinic acetylcholine receptor; SPM, statistical parametric mapping; Vd, volume of distribution; VOI, volume of interest
Received January 20, 2006. Revised April 30, 2006. Accepted May 15, 2006.
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