Support for dopaminergic hypoactivity in restless legs syndrome: a PET study on D2-receptor binding

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.

A family with parkinsonism, essential tremor, restless legs syndrome, and depression

“…27 While the symptoms of RLS may be attributed to alterations in spinal dopaminergic modulation, there is now pathologic and clinical evidence that patients with RLS also display changes in the striatonigral dopaminergic system, and the associative loop involved in decisionmaking. 28,29 Prior imaging studies in RLS have suggested either normal 30 or mildly impaired [31][32][33] presynaptic dopamine function, compatible to the findings reported here.…”

Contribution of Dopamine D1 and D2 Receptors to Amygdala Activity in Human

“…11 C]SCH23390 and [ 11 C]FLB457 studies (Cervenka et al, 2006;Takahashi et al, 2008;Karlsson et al, 2009;McNab et al, 2009), a very small region or a single voxel is susceptible to partial volume effect. Thus, it is recommended that parametric image analysis should be used in combination with ROI analysis.…”

Restless legs syndrome in multiple sclerosis

“…Among the patients with MS, 71 (78%) had relapsingremitting MS (RRMS), 8 (8.8%) had secondary progressive MS (SPMS), 3 (3.3%) had progressive relapsing MS (PRMS), and 9 (9.9%) had primary progressive MS (PPMS). The median number of attacks was 3 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) and the median EDSS score was 3 (0-9) in the MS group (Table 1).…”

“…It has been suggested that hypoactive dopaminergic neurotransmission might contribute to the pathophysiology of RLS (9).…”