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A PET Study on D2-Receptor Binding doi:10.1093/brain/awl163 Brain (2006), 129, 2017–2028 Support for dopaminergic hypoactivity in restless legs syndrome: a PET study on D2-receptor binding Simon Cˇ ervenka,1 Sven E. Pa˚lhagen,2 Robert A. Comley,4 Georgios Panagiotidis,3 Zsolt Csele´nyi,1 Julian C. Matthews,4,5 Robert Y. Lai,6 Christer Halldin1 and Lars Farde1 1Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Karolinska University Hospital Solna, 2Department of Neurology, 3Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska University Hospital Huddinge, Stockholm, Sweden, 4Translational Medicine and Genetics, GlaxoSmithKline, Cambridge, 5The University of Manchester, Wolfson Molecular Imaging Centre, Manchester and 6Neurology Discovery Medicine, GlaxoSmithKline, Harlow, UK Correspondence to: Simon Cˇ ervenka, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Karolinska University Hospital Solna, Building R5, SE-171 76 Stockholm, Sweden E-mail: [email protected] Clinical observations support a central role of the dopamine system in restless legs syndrome (RLS) but previous imaging studies of striatal dopamine D2-receptors have yielded inconclusive results. Extrastriatal dopaminergic function has hitherto not been investigated. Sixteen RLS patients naı¨ve to dopaminergic drugs and sixteen matched control subjects were examined with PET. [11C]Raclopride and [11C]FLB 457 were used to estimate D2-receptor availability in striatum and extrastriatal regions, respectively. Examinations were performed both in the morning (starting between 10:00 and 12:00 h) and evening (starting at 18:00 h). Measures were taken to monitor and control for head movement during data acquisition. In the striatum, patients had significantly higher [11C]raclopride binding potential (BP) values than controls. In extrastriatal regions, [11C]FLB 457 BP was higher in patients than controls, and in the regional analysis the difference was statistically significant in subregions of thalamus and the anterior cingulate cortex. The diurnal variability in BP with [11C]FLB 457 and [11C]raclopride was within the previously reported test–retest reproducibility for both radioligands. The study supports involvement of the dopamine system in both striatal and extrastriatal brain regions in the pathophysiology of RLS. The brain regions where differences in D2-receptor binding were shown are implicated in the regulation of affective and motivational aspects of sensory processing, suggesting a possible pathway for sensory symptoms in RLS. Increased D2-receptor availability in RLS may correspond to higher receptor densities or lower levels of endogenous dopamine. Both interpretations are consistent with the hypothesis of hypoactive dopaminergic neurotransmission in RLS, as increased receptor levels can be owing to receptor upregulation in response to low levels of endogenous dopamine. The results do not support variations in dopamine D2-receptor availability as a correlate to the diurnal rhythm of RLS symptoms. Keywords: brain; human; positron emission tomography; restless legs syndrome Abbreviations: ACC = anterior cingulate cortex; AST = associative striatum; BP = binding potential; DVR = distribution volume ratio; LST = limbic striatum; PET = positron emission tomography; RLS = restless legs syndrome; ROI = regions of interest; SPET = single PET; SMST = sensorimotor striatum Received April 19, 2006. Revised May 10, 2006. Accepted May 22, 2006. Advance Access publication July 1, 2006. Introduction Restless legs syndrome (RLS) is a disorder characterized by rest and in the evening, leading to insomnia and daytime unpleasant leg sensations together with an irresistible inner sleepiness. Using standardized diagnostic criteria (Table 1), urge to move (Ekbom, 1945). Symptoms are worsened at the prevalence of RLS has recently been estimated to be # The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected] 2018 Brain (2006), 129, 2017–2028 S. Cˇ ervenka et al. Table 1 Essential diagnostic criteria for restless legs together, imaging studies so far have not conclusively con- syndrome firmed the postulated role of dopaminergic neurotransmis- (1) An urge to move the legs, usually accompanied or caused by sion in the pathophysiology of RLS. uncomfortable and unpleasant sensations in the legs The phenomenology of RLS indicates that sensory (2) The urge to move or unpleasant sensations begin or worsen symptoms precede motor symptoms. Accordingly, RLS during periods of rest or inactivity such as lying or sitting (3) The urge to move or unpleasant sensations are partially or totally can be viewed as a disorder of sensory perception relieved by movement, such as walking or stretching, at least as (Trenkwalder and Paulus, 2004), and it has previously long as the activity continues been proposed that the pathophysiology is related to (4) The urge to move or unpleasant sensations are worse in the an impairment of central somatosensory processing evening or night than during the day or only occur in the evening (Schattschneider et al., 2004). This disease mechanism sug- or night gests involvement of extrastriatal brain regions implicated in 11 Established by the International Restless Legs Syndrome Study the processing of sensory stimuli. [ C]Raclopride is an Group (Allen et al., 2003). established PET radioligand for examining striatum but not for imaging of the minute dopamine D2-receptor concentrations in extrastriatal regions. The advent of 7.2 and 8.5%, respectively, in two large epidemiological high-affinity radioligands such as [11C]FLB 457 has now studies (Allen et al., 2005; Tison et al., 2005), rendering it made it feasible to quantitatively examine low-density D2- one of the most common neurological disorders. receptor populations using PET (Olsson et al., 1999, 2004). The aetiology and pathophysiology of RLS is poorly The aim of the present PET study was to examine dopa- understood. Most cases are idiopathic, but RLS has also mine D2-receptors in 16 RLS patients and 16 control sub- been shown to occur secondary to other conditions such jects. The radioligands [11C]raclopride and [11C]FLB 457 as iron deficiency, uraemia and pregnancy. Approximately were used to allow for examination of both striatal and 50% of RLS cases report a positive family history, with a extrastriatal brain regions. The circadian component of correlation to early disease onset (Winkelmann et al., 2000, the disorder was addressed by performing measurements 2002; Tison et al., 2005). Three genomic regions have been both in the morning and in the evening. associated to RLS susceptibility, but no candidate genes have been identified (Mata et al., 2006). Material and methods Clinical and pharmacological observations point towards a Subjects central role for the dopamine system in the pathophysiology Sixteen patients with idiopathic RLS (8 males, 8 females) and of RLS. Treatment with dopamine agonists shows efficacy as sixteen age- and sex-matched control subjects were recruited by confirmed by controlled trials (Fulda and Wetter, 2005) advertising in daily newspapers. The study was approved by the while dopamine antagonists worsen symptoms or may Ethics and Radiation Safety committees of the Karolinska Institute. even elicit RLS (Kraus et al., 1999; Wetter et al., 2002; Written informed consent was obtained from all subjects. The Pinninti et al., 2005). Indirect support for a role of the age was 55 6 7 years for patients and 56 6 8 years for controls dopamine system in restlessness is also given by the (these and all subsequent values represented as mean 6 SD). observation that akathisia is a common side-effect of anti- The subjects had no history of significant psychiatric or somatic psychotic drugs that all are dopamine antagonists (Barnes, illness as assessed by medical interview, physical examination, routine blood tests and brain MRI. None of the subjects were 1989; Farde, 1992). nicotine users. Several brain imaging studies of the central dopamine RLS patients were examined by a clinical neurologist who system in RLS have been performed to date. All have focused confirmed the diagnosis according to the IRLSSG diagnostic cri- on the striatum, a brain region receiving dense dopaminergic teria. All patients were naı¨ve to dopaminergic drugs as well as innervation. On the presynaptic side, two PET studies have oipiod agonists. Other medication for RLS or sleep was confined 18 shown reduced utilization of [ F]dopa in the striatum to the occasional use of zolpidem by one of the patients and this was (Turjanski et al., 1999; Ruottinen et al., 2000) while one discontinued >5 half-lives prior to the first PET examination. study showed no difference (Trenkwalder et al., 1999b). The symptom duration was 27 6 12 years and heritability for No difference in binding to the dopamine transporter has RLS, defined as at least one first-order relative being affected, been found in studies employing single PET (SPET) was observed in 9 of the 16 cases. In order to confirm study (Eisensehr et al., 2001; Michaud et al., 2002; Tribl et al., eligibility, RLS symptoms in patients were rated on the day of 2002; Linke et al., 2004; Mrowka et al., 2005). Studies on the first PET examination using the IRLSSG severity rating scale (Walters et al., 2003). The average rating was 18.5 6 3.9. Individual radioligand binding to D2-receptors, a marker primarily
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