3-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile and Parkinson-Disease

In the last decades, the main focus of molecular imaging of Parkinson's disease has been on non-dopaminergic systems involved in the disease alongside the pathognomonic dopaminergic changes. Molecular imaging can detect, in vivo, both presynaptic and postsynaptic serotonergic changes in the brain and has played a key role in elucidating the pathophysiology of the serotonergic system in Parkinson's disease. Alterations in the serotonergic system may happen very early in the course of the disease and have shown a leading role in the development of tremor and dyskinesias, and in several non-motor symptoms, including sleep, cognitive and neuropsychiatric disturbances. These studies increasingly recognize that the regional topography of serotonergic brain areas associates with specific dysfunctions. In parallel with this trend, more recent molecular serotonergic imaging approaches are investigating serotonergic modulatory treatment and their contributions to the improvement of cognitive functions. In this review, we discussed post-mortem, preclinical and imaging evidence of serotonergic system changes in Parkinson's disease, and described how disease-specific serotonergic changes are relevant for motor and non-motor symptoms and complications. Future directions of serotonergic imaging have been also described alongside with the novel findings on the role of serotonergic system in asymptomatic LRRK2 carriers.

Topics: Aniline Compounds; Animals; Cognition Disorders; Depression; Humans; Molecular Imaging; Parkinson Disease; Positron-Emission Tomography; Receptors, Serotonin; Serotonin Plasma Membrane Transport Proteins; Sleep Wake Disorders; Sulfides; Tremor

Brain uptake of [(18)F]FDOPA, measured with PET, reflects the activity of aromatic amino acid decarboxylase, an enzyme largely expressed in monoaminergic nerve terminals. This enzyme catalyzes a number of decarboxylation reactions including conversion of l-dopa into dopamine and 5-hydroxytryptophan into serotonin. For more than 20years [(18)F]FDOPA PET has been used to assess dopaminergic nigrostriatal dysfunction in patients with Parkinson's disease (PD). More recently, however, [(18)F]FDOPA PET has also been employed as a marker of serotoninergic and noradrenergic function in PD patients. In this study, we provide further evidence in support of the view that [(18)F]FDOPA PET can be used to evaluate the distribution and the function of serotoninergic systems in the brain. Eighteen patients with PD were investigated with both [(18)F]FDOPA and [(11)C]DASB PET, the latter being a marker of serotonin transport (SERT) availability. We then assessed the relationship between measurements of the two tracers within brain serotoninergic structures. [(18)F]FDOPA uptake in the median raphe nuclei complex of PD patients was significantly correlated with SERT availability in the same structure. Trends towards significant correlations between [(18)F]FDOPA Ki values and [(11)C]DASB binding values were also observed in the hypothalamus and the anterior cingulate cortex, suggesting a serotoninergic contribution to [(18)F]FDOPA uptake in these regions. Conversely, no correlations were found in brain structures with mixed dopaminergic, serotoninergic and noradrenergic innervations, or with predominant dopaminergic innervation. These findings provide evidence that [(18)F]FDOPA PET represents a valid marker of raphe serotoninergic function in PD and supports previous studies where [(18)F]FDOPA PET has been used to assess serotoninergic function in PD.

Topics: Aged; Aniline Compounds; Biological Availability; Dihydroxyphenylalanine; Female; Humans; Male; Parkinson Disease; Positron-Emission Tomography; Radiopharmaceuticals; Raphe Nuclei; Serotonin Plasma Membrane Transport Proteins; Sulfides; Tissue Distribution

This study investigated whether abnormalities in serotonin transporter binding occur in Parkinson's disease (PD) patients with concurrent depression. We estimated serotonin transporter levels in seven clinically depressed early-stage PD patients and in seven healthy matched-control subjects during a single positron emission tomography (PET) scan with the serotonin transporter radioligand, [(11)C]DASB. Depressed PD patients displayed a wide-spread increase (8-68%) in [(11)C]DASB specific binding outside of the striatum, which was significant in dorsolateral (37%) and prefrontal (68%) cortices. Elevated [(11)C]DASB binding was positively correlated with depressive symptoms but not with disease severity or duration. Compatible with recent PET/[(11)C]DASB findings in major depression, the present preliminary data suggest that increased [(11)C]DASB binding, possibly reflecting greater serotonin transporter density (up-regulation), might be a pathological feature of depression in Parkinson's disease-and possibly a characteristic of depressive illness in general.

Topics: Aged; Aniline Compounds; Case-Control Studies; Depression; Female; Humans; Male; Middle Aged; Parkinson Disease; Positron-Emission Tomography; Prefrontal Cortex; Protein Binding; Psychiatric Status Rating Scales; Serotonin Plasma Membrane Transport Proteins; Statistics, Nonparametric; Sulfides