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Abstract
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 naïve 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.
Highlights
Restless legs syndrome (RLS) is a disorder characterized by unpleasant leg sensations together with an irresistible inner urge to move (Ekbom, 1945)
Subjective symptoms as assessed after evening examinations were higher for RLS patient than control subjects both for [11C]raclopride (3.2 versus 0.6, P < 0.005) and [11C]FLB 457 (4.8 versus 0.9, P < 0.001)
Previous molecular imaging studies of striatal dopamine D2-receptors in RLS patients have shown reduced radioligand binding or no difference when compared with control subjects
Summary
Restless legs syndrome (RLS) is a disorder characterized by unpleasant leg sensations together with an irresistible inner urge to move (Ekbom, 1945). 7.2 and 8.5%, respectively, in two large epidemiological studies (Allen et al, 2005; Tison et al, 2005), rendering it one of the most common neurological disorders. 50% of RLS cases report a positive family history, with a correlation to early disease onset (Winkelmann et al, 2000, 2002; Tison et al, 2005). Three genomic regions have been associated to RLS susceptibility, but no candidate genes have been identified (Mata et al, 2006)
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