In vivo dopaminergic and serotonergic dysfunction in DCTN1 gene mutation carriers

Abstract

Introduction: We used positron emission tomography (PET) to assess dopaminergic and serotonergic terminal density in three subjects carrying a mutation in the DCT1 gene, two clinically affected with Perry syndrome.

Methods: All subjects had brain imaging using 18F-6-fluoro-l-dopa (FDOPA, dopamine synthesis and storage), (+)-11C-dihydrotetrabenazine (DTBZ, vesicular monoamine transporter type 2), and 11C-raclopride (RAC, dopamine D2/D3 receptors). One subject also underwent PET with 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB, serotonin transporter).

Results: FDOPA-PET and DTBZ-PET in the affected individuals showed a reduction of striatal tracer uptake. Also, RAC-PET showed higher uptake in these area. DASB-PET showed significant uptake changes in left orbitofrontal cortex, bilateral anterior insula, left dorsolateral prefrontal cortex, left orbitofrontal cortex, left posterior cingulate cortex, left caudate, and left ventral striatum.

Conclusions: Our data showed evidence of both striatal dopaminergic and widespread cortical/subcortical serotonergic dysfunctions in individuals carrying a mutation in the DCTN1 gene.

Keywords: Perry syndrome; dopaminergic dysfunction; dynactin gene; positron emission tomography; serotonergic dysfunction.

Figure 1

Figure 1. [^¹¹C]-DASB positron emission tomography study in an affected subject with genetically-proven Perry syndrome compared to healthy control subjects (n=6). Bar charts represent (A) Cortical areas, (B) Subcortical areas, and (C) Brainstem. Legend: Amyg = amygdala; AntCing = anterior cingulate; AntIns = anterior insula; Caud = caudate; DLPFC = dorsolateral prefrontal cortex; HypTh = hypothalamus; MidBr = midbrain; OFC = orbitofrontal cortex; PostCing = posterior cingulate; Put = putamen; SN = substantia nigra; Thal = thalamus; VS = ventral striatum. An asterisk (*) denotes values outside 2 standard deviations compared to control values. For midline structures (pons/midbrain/medulla) only a single value is reported.

Figure 1

Figure 1. [^¹¹C]-DASB positron emission tomography study in an affected subject with genetically-proven Perry syndrome compared to healthy control subjects (n=6). Bar charts represent (A) Cortical areas, (B) Subcortical areas, and (C) Brainstem. Legend: Amyg = amygdala; AntCing = anterior cingulate; AntIns = anterior insula; Caud = caudate; DLPFC = dorsolateral prefrontal cortex; HypTh = hypothalamus; MidBr = midbrain; OFC = orbitofrontal cortex; PostCing = posterior cingulate; Put = putamen; SN = substantia nigra; Thal = thalamus; VS = ventral striatum. An asterisk (*) denotes values outside 2 standard deviations compared to control values. For midline structures (pons/midbrain/medulla) only a single value is reported.

Figure 1

Figure 1. [^¹¹C]-DASB positron emission tomography study in an affected subject with genetically-proven Perry syndrome compared to healthy control subjects (n=6). Bar charts represent (A) Cortical areas, (B) Subcortical areas, and (C) Brainstem. Legend: Amyg = amygdala; AntCing = anterior cingulate; AntIns = anterior insula; Caud = caudate; DLPFC = dorsolateral prefrontal cortex; HypTh = hypothalamus; MidBr = midbrain; OFC = orbitofrontal cortex; PostCing = posterior cingulate; Put = putamen; SN = substantia nigra; Thal = thalamus; VS = ventral striatum. An asterisk (*) denotes values outside 2 standard deviations compared to control values. For midline structures (pons/midbrain/medulla) only a single value is reported.

Figure 2

¹⁸F-6-fluoro-L-dopa (FDOPA), (+)-¹¹C-dihydrotetrabenazine (DTBZ), ¹¹C-raclopride (RAC), and ¹¹C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) imaging panel showing a genetically-proven Perry syndrome subject (right) as compared to an approximately age-matched control (left). FDOPA uptake (A) and DTBZ binding (B) are reduced in the Perry subject compared to the control subject (left). In contrast, RAC binding is normal in the Perry subject (C). There are widespread reductions in DASB binding in the Perry subject (D). (A) through (C) are axial images, (D) is sagittal.