Extrastriatal binding of [123I]FP-CIT in the thalamus and pons: gender and age dependencies assessed in a European multicentre database of healthy controls

Koch, Walter; Unterrainer, Marcus; Xiong, Guoming; Bartenstein, Peter; Diemling, Markus; Varrone, Andrea; Dickson, John; Tossici-Bolt, Livia; Séra, Teréz; Asenbaum, S.; Booij, Jan; Kapucu, Özlem; Kluge, Andreas; Ziebell, Morten; Darcourt, Jacques; Nobili, Flavio; Pagani, Marco; Hesse, Swen; Borght, Thierry Vander; Laere, Koen Van; Tatsch, Klaus; Fougère, Christian la

doi:10.1007/s00259-014-2785-8

Cited by 65 publications

(68 citation statements)

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“…In addition, it cannot be excluded that the binding in cortical regions that correlates with ventral midbrain binding is partly from SERT. However, 123 I-FP-CIT has clearly the highest affinity for DAT, and in striatal regions the signal is mainly from DAT (11,12).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the neurotransmitter system under study depends on the relative density (and ligand affinity) of the monoamine transporters in the given brain region. For instance, in the dopamine-rich striatum 123 I-FP-CIT binding can be considered specific for DAT, but the binding is mainly for SERT in the thalamus and raphe nuclei (12). However, the signal-to-noise ratio of 123 I-FP-CIT in the extrastriatal regions is clearly lower than in the DAT-rich striatum, which has limited the extrastriatal use of 123 I-FP-CIT.…”

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confidence: 99%

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Dorsal-to-Ventral Shift in Midbrain Dopaminergic Projections and Increased Thalamic/Raphe Serotonergic Function in Early Parkinson Disease

et al. 2015

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Loss of nigrostriatal neurons leading to dopamine depletion in the dorsal striatum is the pathologic hallmark of Parkinson disease contributing to the primary motor symptoms of the disease. However, Parkinson pathology is more widespread in the brain, affecting also other dopaminergic pathways and neurotransmitter systems, but these changes are less well characterized. This study aimed to investigate the mesencephalic striatal and extrastriatal dopaminergic projections together with extrastriatal serotonin transporter binding in Parkinson disease. Methods: Two hundred sixteen patients with Parkinson disease and 204 control patients (patients without neurodegenerative parkinsonism syndromes and normal SPECT imaging) were investigated with SPECT using the dopamine/ serotonin transporter ligand 123 I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ( 123 I-FP-CIT) in the clinical setting. The group differences and midbrain correlations were analyzed voxel by voxel over the entire brain. Results: We found that Parkinson patients had lower 123 I-FP-CIT uptake in the striatum and ventral midbrain but higher uptake in the thalamus and raphe nuclei than control patients. In patients with Parkinson disease, the correlation of the midbrain tracer uptake was shifted from the putamen to widespread corticolimbic areas. All findings were highly significant at the voxel level familywise error-corrected P value of less than 0.05. Conclusion: Our findings show that Parkinson disease is associated not only with the degeneration of the nigrostriatal dopamine neurotransmission, but also with a parallel shift toward mesolimbic and mesocortical function. Furthermore, Parkinson disease patients seem to have upregulation of brain serotonin transporter function at the early phase of the disease.Key Words: dopamine; serotonin; SPECT; midbrain; raphe nuclei J Nucl Med 2015; 56:1036 56: -1041 56: DOI: 10.2967 Par kinson disease (PD) is a neurodegenerative condition characterized by the progressive accumulation of Lewy body inclusions beginning from the medulla and olfactory nuclei and gradually spreading through the midbrain to the neocortex (1). In the human brain, there are 2 major dopamine systems. The nigrostriatal pathway originates from the substantia nigra (SN) pars compacta (region A9) projecting to the putamen, and the ventral dopamine pathways (mesolimbic and mesocortical pathways) originate from the ventral tegmental area (VTA, A10) and innervate the limbic system and neocortex. PD pathology shows regional selectivity within the SN affecting the most ventrolateral-tier neurons that mainly project to the dorsal putamen (2), and molecular in vivo imaging studies have shown corresponding posterior-to-anterior gradient in the degeneration of the dopamine function within the striatum (3). However, to the best of our knowledge, no prior studies have investigated the midbrain projections within the dopamine system in PD.PD is primarily treated with medications that enhance the brain dopamine function, but not all symptoms...

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Section: Discussionmentioning

confidence: 99%

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Dorsal-to-Ventral Shift in Midbrain Dopaminergic Projections and Increased Thalamic/Raphe Serotonergic Function in Early Parkinson Disease

et al. 2015

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“…However, there is at present no evidence of associations between SLC6A3 genotype and DAT availability in extrastriatal areas on the basis of human PET/SPECT studies. Additionally, DAT expression outside the striatum is typically quite low (Ciliax et al, 1999) and highly variable between individuals (Koch et al, 2014).…”

Section: Pharmacogenetic Findingsmentioning

confidence: 99%

Methylphenidate Effects on Brain Activity as a Function of SLC6A3 Genotype and Striatal Dopamine Transporter Availability

Kasparbauer

Rujescu²,

Riedel

et al. 2014

Neuropsychopharmacol

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We pharmacologically challenged catecholamine reuptake, using methylphenidate, to investigate its effects on brain activity during a motor response inhibition task as a function of the 3 0 -UTR variable number of tandem repeats (VNTR) polymorphism of the dopamine transporter (DAT) gene (SLC6A3) and the availability of DATs in the striatum. We measured the cerebral hemodynamic response of 50 healthy males during a Go/No-Go task, a measure of cognitive control, under the influence of 40 mg methylphenidate and placebo using 3T functional magnetic resonance imaging. Subjects were grouped into 9-repeat (9R) carriers and 10/10 homozygotes on the basis of the SLC6A3 VNTR. During successful no-go trials compared with oddball trials, methylphenidate induced an increase of blood oxygen level-dependent (BOLD) signal for carriers of the SLC6A3 9R allele but a decrease in 10/10 homozygotes in a thalamocortical network. The same pattern was observed in caudate and inferior frontal gyrus when successful no-go trials were compared with successful go trials. We additionally investigated in a subset of 35 participants whether baseline striatal DAT availability, ascertained with 123 I-FP-CIT single photon emission computed tomography, predicted the amount of methylphenidate-induced change in hemodynamic response or behavior. Striatal DAT availability was nominally greater in 9R carriers compared with 10/10 homozygotes (d ¼ 0.40), in line with metaanalyses, but did not predict BOLD or behavioral changes following MPH administration. We conclude that the effects of acute MPH administration on brain activation are dependent on DAT genotype, with 9R carriers showing enhanced BOLD following administration of a prodopaminergic compound.

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“…A region-of-interest (ROI) approach is based on a semi-quantitative analysis of the striatal region compared to a reference (occipital) region, after normalizing all images to a standardized 123 I-FP-CIT template derived from healthy subjects (BRASS software, Brain Registration & Analysis Software Suite, Hermes Medical Solutions, Stockholm, Sweden) 18 . Furthermore, a whole-brain approach based on Statistical Parametric Mapping for SPECT 123 I-FP-CIT imaging has been proposed 19-21 , with the possibility to perform voxelwise studies on different groups of subjects with different statistical paradigms, and with the possibility to explore extrastriatal regions 22-25 .…”

Section: Introductionmentioning

confidence: 99%

Source-Based Morphometry Multivariate Approach to Analyze [123I]FP-CIT SPECT Imaging

et al. 2017

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Background 123I-FP-CIT (DaTSCAN®) SPECT imaging is widely used to study neurodegenerative parkinsonism, with the evaluation of presynaptic dopamine transporter (DAT) in striatal regions. Beyond DAT, 123I-FP-CIT may be also considered for other monoaminergic systems, in particular serotonin transporter (SERT). Independent Component Analysis (ICA) implemented in Source-Based Morphometry (SBM), a multivariate approach, represents an alternative method to explore monoaminergic neurotransmission, studying the relationship among voxels, and grouping them into “metabolic” neural networks. Methods One-hundred forty-three subjects (84 with Parkinson’s disease (PD) and 59 control individuals (CG)) underwent DATSCAN® imaging. The 123I-FP-CIT binding was evaluated by the multivariate SBM approach, as well as by region-of-interest (ROI) (caudate/putamen) (BRASS software) and whole-brain voxelwise univariate (Statistical Parametric Mapping, SPM) approaches. Results As compared to univariate approaches (BRASS and SPM), which only demonstrated striatal 123I-FP-CIT binding reduction in the PD group, SBM identified six sources of non-artifactual origin, including basal ganglia and cortical regions as well as brainstem. Among them, three sources (basal ganglia and cortical regions) presented loading scores (as index of 123I-FP-CIT binding) significantly different between PD and CG. Notably, even though not significantly different between PD and CG, the remaining three non-artifactual sources were characterized by a predominant frontal, brainstem and occipito-temporal involvement. Discussion The concept of source blind separation by the application of ICA (as implemented in SBM) represents a feasible approach to be considered in 123I-FP-CIT (DaTSCAN®) SPECT imaging. Taking advantage of this multivariate analysis, specific patterns of variance can be identified (involving either striatal or extrastriatal regions) that could be useful in differentiating neurodegenerative parkinsonisms.

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Extrastriatal binding of [123I]FP-CIT in the thalamus and pons: gender and age dependencies assessed in a European multicentre database of healthy controls

Cited by 65 publications

References 54 publications

Dorsal-to-Ventral Shift in Midbrain Dopaminergic Projections and Increased Thalamic/Raphe Serotonergic Function in Early Parkinson Disease

Dorsal-to-Ventral Shift in Midbrain Dopaminergic Projections and Increased Thalamic/Raphe Serotonergic Function in Early Parkinson Disease

Methylphenidate Effects on Brain Activity as a Function of SLC6A3 Genotype and Striatal Dopamine Transporter Availability

Source-Based Morphometry Multivariate Approach to Analyze [123I]FP-CIT SPECT Imaging

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