Reduced striatal D2 receptor binding in myoclonus–dystonia

Beukers, Richard J.; Booij, Jan; Weisscher, Nadine; Zijlstra, Fleur; Amelsvoort, Thérèse van; Tijssen, Marina A. J.

doi:10.1007/s00259-008-0924-9

Cited by 54 publications

(42 citation statements)

References 32 publications

(38 reference statements)

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“…Previously, our group showed statistically significantly lower striatal dopamine D2 receptor (D2R) binding in M–D patients, possibly due to decreased D2R availability or increased levels of endogenous dopamine and consequently competitive D2R occupancy (Beukers et al, 2009), consistent with a mouse model showing increased striatal dopamine and metabolites in SGCE knockout mice (Yokoi et al, 2006). …”

Section: Introductionsupporting

confidence: 66%

Deep Brain Stimulation of the Pallidum is Effective and Might Stabilize Striatal D2 Receptor Binding in Myoclonus–Dystonia

Beukers¹,

Contarino²,

Speelman³

et al. 2012

Front. Neur.

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Purpose: To assess clinical efficacy of deep brain stimulation (DBS) of the pallidum in Myoclonus–Dystonia (M–D) patients, and to compare pre- and post-operative striatal dopamine D2 receptor availability. Methods: Clinical parameters were scored using validated rating scales for myoclonus and dystonia. Dopamine D2 receptor binding of three patients was studied before surgery and approximately 2 years post-operatively using 123-I-iodobenzamide Single Photon Emission Computed Tomography. Two patients who did not undergo surgery served as controls. Results: Clinically, the three M–D patients improved 83, 17, and 100%, respectively on the myoclonus rating scale and 78, 23, and 65% on the dystonia rating scale after DBS. Dopamine D2 receptor binding did not change after surgery. In the two control subjects, binding has lowered further. Conclusion: These findings confirm that DBS of the pallidum has beneficial effects on motor symptoms in M–D and suggest this procedure might stabilize dopamine D2 receptor binding.

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Section: Introductionsupporting

confidence: 66%

Deep Brain Stimulation of the Pallidum is Effective and Might Stabilize Striatal D2 Receptor Binding in Myoclonus–Dystonia

Beukers¹,

Contarino²,

Speelman³

et al. 2012

Front. Neur.

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“…30,31 Moderate expression levels of the major brain-specific SGCE isoform in the striatum and lowest expression levels in the globus pallidus were found in all control subjects. We propose that observed striatal changes may be secondary owing to abnormal cerebellar signaling.…”

Section: Discussionmentioning

confidence: 98%

SGCE isoform characterization and expression in human brain: implications for myoclonus–dystonia pathogenesis?

et al. 2010

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Myoclonus-dystonia (M-D) is a neurological movement disorder with involuntary jerky and dystonic movements as major symptoms. About 50% of M-D patients have a mutation in e-sarcoglycan (SGCE), a maternally imprinted gene that is widely expressed. As little is known about SGCE function, one can only speculate about the pathomechanisms of the exclusively neurological phenotype in M-D. We characterized different SGCE isoforms in the human brain using ultra-deep sequencing. We show that a major brain-specific isoform is differentially expressed in the human brain with a notably high expression in the cerebellum, namely in the Purkinje cells and neurons of the dentate nucleus. Its expression was low in the globus pallidus and moderate to low in caudate nucleus, putamen and substantia nigra. Electrophysiological studies in man suggest that myoclonic symptoms are of subcortical origin. [1][2][3] In general, dystonia is thought to arise from dysfunction of the basal ganglia. 4 About 50% of M-D patients who were classified as definite M-D carry a mutation in the widely expressed e-sarcoglycan (SGCE). [5][6][7] The genetic cause in the remaining patients is still unclear. A second locus has been reported in one large M-D family (DYT15, 18p11), but no gene has been identified yet. 8,9 SGCE is part of the sarcoglycan family that consists of N-glycosylated transmembrane proteins. Six different sarcoglycans have been identified so far (a-, b-, g-, d-, e-and z-), but little is known about the function of particular sarcoglycan members and their function in different tissues. 10 In muscles, sarcoglycans form a heterotetrameric complex that is constituent of the dystrophinassociated protein complex. This complex mediates the structural stability of the plasma membrane and interactions between the extracellular matrix and the cytoskeleton. 11 Mutations in other sarcoglycans, a-, b-, g-and d-sarcoglycan, lead to different forms of limb-girdle muscular dystrophy, characterized by progressive muscle weakness. 10 Little is known about composition and function of the dystrophin-associated protein complex in the brain. SGCE is highly homologous to a-sarcoglycan, 12 but no muscle

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“…This could be consistent with a hyperdopaminergic state in the striatum and/or with a reduced number of D2/3 receptors. Previous reports have been ambiguous about D2/3 receptor binding in dystonia, although reduced binding has been more commonly reported [13, 15, 37]. …”

Section: Discussionmentioning

confidence: 99%

The relationship between the dopaminergic system and depressive symptoms in cervical dystonia

Zoons

Tijssen

Dreissen

et al. 2017

Eur J Nucl Med Mol Imaging

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PurposeCervical dystonia (CD) is associated with tremor/jerks (50%) and psychiatric complaints (17–70%). The dopaminergic system has been implicated in the pathophysiology of CD in animal and imaging studies. Dopamine may be related to the motor as well as non-motor symptoms of CD. CD is associated with reduced striatal dopamine D2/3 (D2/3) receptor and increased dopamine transporter (DAT) binding. There are differences in the dopamine system between CD patients with and without jerks/tremor and psychiatric symptoms.MethodsPatients with CD and healthy controls underwent neurological and psychiatric examinations. Striatal DAT and D2/3 receptor binding were assessed using [123I]FP-CIT and [123I]IBZM SPECT, respectively. The ratio of specific striatal to non-specific binding (binding potential; BPND) was the outcome measure.ResultsTwenty-seven patients with CD and 15 matched controls were included. Nineteen percent of patients fulfilled the criteria for a depression. Striatal DAT BPND was significantly lower in depressed versus non-depressed CD patients. Higher DAT BPND correlated significantly with higher scores on the Unified Myoclonus Rating Scale (UMRS). The striatal D2/3 receptor BPND in CD patients showed a trend towards lower binding compared to controls. The D2/3 BPND was significantly lower in depressed versus non-depressed CD patients. A significant correlation between DAT and D2/3R BPND was found in both in patients and controls.ConclusionsAlterations of striatal DAT and D2/3 receptor binding in CD patients are related mainly to depression. DAT BPND correlates significantly with scores on the UMRS, suggesting a role for dopamine in the pathophysiology of tremor/jerks in CD.

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Reduced striatal D2 receptor binding in myoclonus–dystonia

Abstract: Our findings are consistent with the theory of reduced dopamine D(2) receptor (D2R) availability in dystonia, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out.

Cited by 54 publications

References 32 publications

Deep Brain Stimulation of the Pallidum is Effective and Might Stabilize Striatal D2 Receptor Binding in Myoclonus–Dystonia

Deep Brain Stimulation of the Pallidum is Effective and Might Stabilize Striatal D2 Receptor Binding in Myoclonus–Dystonia

SGCE isoform characterization and expression in human brain: implications for myoclonus–dystonia pathogenesis?

The relationship between the dopaminergic system and depressive symptoms in cervical dystonia

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