SERT-to-DAT ratios in early Parkinson’s disease do not correlate with the development of dyskinesias

Suwijn, Sven R.; Berendse, Henk W.; Verschuur, Constant V. M.; Winogrodzka, Ania; Bie, Rob M.A. de; Booij, Jan

doi:10.1186/2191-219x-3-44

Cited by 10 publications

(5 citation statements)

References 31 publications

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“…Finally, positron emission tomography imaging of patients who developed graft‐induced dyskinesias suggest that the role of 5‐HT innervation in LID is dependent on the extent of residual dopaminergic function . However, recent single‐photon emission computed tomography (SPECT) study of early‐stage PD patients found that baseline SERT/DAT ratios did not correlate with the development of LID later in the disease . Our data confirm this observation in advanced PD, because no difference was observed in striatal SERT/DAT ratio between patients with and without LID in this study (Supplemental Data Table 3).…”

Section: Discussionsupporting

confidence: 79%

“…However, recent single-photon emission computed tomography (SPECT) study of early-stage PD patients found that baseline SERT/DAT ratios did not correlate with the development of LID later in the disease. 39 Our data confirm this observation in advanced PD, because no difference was observed in striatal SERT/DAT ratio between patients with and without LID in this study (Supplemental Data Table 3).…”

Section: H E S H I R E E T a Lsupporting

confidence: 88%

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Serotonergic markers in Parkinson's disease and levodopa‐induced dyskinesias

et al. 2015

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Preclinical animal models implicate serotonin neurons in the pathophysiology of levodopa (l-dopa)-induced dyskinesias in Parkinson's disease (PD), but effective treatment remains elusive. We examined the relationship between serotonin and l-dopa-induced dyskinesias in a pathologically confirmed cohort of PD patients. We obtained brain tissue from 44 PD cases and 17 age-matched controls and assessed monoamine levels and the serotonin and dopamine transporters in the striatum, and the extent of dopaminergic and serotonergic cell preservation in the substantia nigra (SN) and the dorsal raphe nuclei (DRN), respectively. As expected, PD patients demonstrated a severe loss of all dopaminergic markers, including dopamine (P < 0.0001) and the dopamine transporter (P < 0.0001) in the striatum, and dopaminergic neurons (P < 0.001) in the SN, compared with controls. Marked serotonin loss was observed in the caudate (but not putamen) in PD patients compared with controls (P < 0.001), but no difference was found in the levels of the serotonin transporter in the striatum or density of serotonergic neurons in the DRN between these groups, suggesting a functional but not structural change in the serotonergic system in PD. No difference was seen in levels of serotonergic and dopaminergic markers in the striatum between PD patients with and without dyskinesias, or between cases separated according to the clinical severity of their dyskinesias. The absence of a correlation between striatal serotonin markers and the incidence and severity of l-dopa-induced dyskinesias suggests that an intact and functioning serotonergic system is not a risk factor for developing dyskinesias in PD.

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Section: Discussionsupporting

confidence: 79%

Section: H E S H I R E E T a Lsupporting

confidence: 88%

Serotonergic markers in Parkinson's disease and levodopa‐induced dyskinesias

et al. 2015

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“…The authors showed that imbalanced ratios do not predict the development of LIDs in early stages of the disease, but hypothesized that imbalance ratios may occur at later stages of PD. 30 Our study suggests that the putaminal SERT-to-DAT terminals ratio is a good index to quantify in vivo the serotonergic over dopaminergic terminals' activity. Using PET and SPECT imaging, we have shown that the presence of LIDs is related to an imbalanced serotonergic-over-dopaminergic terminals density ratio in the putamen.…”

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confidence: 99%

Serotonin-to-dopamine transporter ratios in Parkinson disease

et al. 2016

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Objective: To investigate whether a serotonin-to-dopamine terminal ratio is related to the appearance of dyskinesias in patients with Parkinson disease (PD).Methods: Twenty-eight patients with idiopathic PD (17 with levodopa-induced dyskinesias [LIDs], 11 without dyskinesias) and 12 age-matched healthy controls were studied with PET and 5[11 C]-3-amino-4-(2-dimethylaminomethylphenyl-sulfanyl)-benzonitrile ( 11 C-DASB) and with SPECT and [ 123 I]N-w-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl)nortropane ( 123 I-ioflupane), which are in vivo specific markers of the serotonin and dopamine transporters' availability, respectively. We have employed a simplified reference tissue model for the quantification of 11 C-DASB, whereas a semiquantification approach was used for 123 I-ioflupane data. We calculated 11 C-DASB binding to 123 I-ioflupane uptake ratios for the caudate and the putamen.Results: Patients with PD showed striatal decreases in 11 C-DASB binding potential (p , 0.01) and in 123 I-ioflupane mean uptake (p , 0.001) compared to controls. The mean 11 C-DASB binding to 123 I-ioflupane uptake ratio in the putamen was 0.779 (increased by 75.8% of the controls' mean) for the nondyskinetic group and 0.901 (increased by 103.4% of the controls' mean) for the patients with dyskinesias. There was a statistically significant difference (p , 0.001) in 11 C-DASB binding to 123 I-ioflupane uptake ratio in the putamen between the group of patients with and without dyskinesias. Higher 11 C-DASB to 123 I-ioflupane binding ratios correlated with longer disease duration for the 28 patients with PD (r 5 0.52; p , 0.01).Conclusions: Serotonin-to-dopamine transporter binding ratio increases as PD progresses and patients experience LIDs. Our findings suggest that, when the dopaminergic innervation in the striatum is critically low, the serotonergic system plays an important role in development of LIDs. Studies in the animal model of Parkinson disease (PD)1 as well as in humans 2-4 have indicated that degeneration of dopaminergic presynaptic terminals in the striatum is critical in the development of L-dopa-induced dyskinesias (LIDs). Due to the progressive degeneration, striatal dopaminergic terminals lose their dopamine storage capacity and the ability to maintain a stable dopamine release rate in the synapse. 5 Serotonergic terminals have been found capable of converting exogenous levodopa into dopamine, store it in synaptic vesicles, and release it in an activity-dependent manner. [6][7][8][9] The above studies propose that serotonergic terminals in the degenerating striatum are responsible for mishandling exogenous levodopa and exacerbating dyskinesia in the animal model 10-12 and PD.13 Accordingly, the presence of dyskinesia could be a reflection of serotonergic over

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“…However, a study using post-mortem brains of PD patients measured a significant decrease of SERT levels only in the caudate nucleus and not in the putamen, while no difference in SERT levels was observed between PD patients with or without LID (Kish et al, 2008). Moreover, SERT-to-DAT ratios in early-stage and untreated parkinsonian patients were shown not to correlate with the future development of LID (Suwijn et al, 2013).…”

Section: Effects Of a Chronic Treatment With L-dopa And Mpep On Basalmentioning

confidence: 86%