Dopaminergic denervation using [123I]-FPCIT and pain in Parkinson's disease: a correlation study.

In patients with Parkinson's disease (PD), abnormal activations of nociceptive brain areas and lowered pain thresholds were reported, probably reflecting a central modification of pain processing. The aim of this study was to investigate the possible correlation between the striatal and extrastriatal dopaminergic system and pain threshold in PD patients. We included 25 PD patients with various intensities of central pain (visual analog scale). Subjective pain threshold (thermotest) and a motor examination (UPDRS III) were performed. Patients underwent SPECT imaging with [123I]-FP-CIT. We analyzed the correlation between [123I]-FP-CIT binding and subjective pain threshold, using a simple linear regression model for striatal uptake and a voxel-based approach for extrastriatal uptake. The covariables were age, sex, duration of PD, and UPDRS motor score. A pain matrix mask was also used to identify clusters in relation with pain matrix. Striatal analysis revealed that [123I]-FP-CIT binding was negatively correlated with age (p = 0.02), duration of PD (p = 0.0002) and UPDRS motor score (p = 0.006), but no correlation with pain threshold was observed. The extrastriatal analysis showed a positive correlation between [123I]-FP-CIT binding and subjective heat pain threshold for the left posterior cingulate cortex (PCC) (p < 0.001) and negative correlations for the right secondary visual cortex (p < 0.001) and left insula (p < 0.001). When applying the pain matrix mask, correlations remained significant only in the left PCC and the left insula. We suggest that pain perception abnormalities in PD are not directly related to striatal dopaminergic dysfunction. Painful sensations may be related to extrastriatal monoaminergic systems.

Radiolabeling of [18F]-fluoroethylnormemantine and initial in vivo evaluation of this innovative PET tracer for imaging the PCP sites of NMDA receptors.

INTRODUCTION: The N-methyl-D-aspartate receptor (NMDAr) is an ionotropic receptor that mediates excitatory transmission. NMDAr overexcitation is thought to be involved in neurological and neuropsychiatric disorders such as Alzheimer disease and schizophrenia. We synthesized [(18)F]-fluoroethylnormemantine ([(18)F]-FNM), a memantine derivative that binds to phencyclidine (PCP) sites within the NMDA channel pore. These sites are primarily accessible when the channel is in the active and open state. METHODS: Radiosynthesis was carried out using the Raytest® SynChrom R&D fluorination module. Affinity of this new compound was determined by competition assay. We ran a kinetic study in rats and computed a time-activity curve based on a volume-of-interest analysis, using CARIMAS® software. We performed an ex vivo autoradiography, exposing frozen rat brain sections to a phosphorscreen. Adjacent sections were used to detect NMDAr by immunohistochemistry with an anti-NR1 antibody. As a control of the specificity of our compound for NMDAr, we used a rat anesthetized with ketamine. Correlation analysis was performed with ImageJ software between signal of autoradiography and immunostaining. RESULTS: Fluorination yield was 10.5% (end of synthesis), with a mean activity of 3145 MBq and a specific activity above 355 GBq/µmol. Affinity assessment allowed us to determine [(19)F]-FNM IC50 at 6.1 10(-6)M. [(18)F]-FMN concentration gradually increased in the brain, stabilizing at 40 minutes post injection. The brain-to-blood ratio was 6, and 0.4% of the injected dose was found in the brain. Combined ex vivo autoradiography and immunohistochemical staining demonstrated colocalization of NMDAr and [(18)F]-FNM (r=0.622, p<0.0001). The highest intensity was found in the cortex and cerebellum, and the lowest in white matter. A low and homogeneous signal corresponding to unspecific binding was observed when PCP sites were blocked with ketamine. CONCLUSIONS: [(18)F]-FNM appears to be a promising tracer for imaging NMDAr activity for undertaking preclinical studies in perspective of clinical detection of neurological or neuropsychological disorders.

Insight on AV-45 binding in white and grey matter from histogram analysis: a study on early Alzheimer's disease patients and healthy subjects.

PURPOSE: AV-45 amyloid biomarker is known to show uptake in white matter in patients with Alzheimer's disease (AD), but also in the healthy population. This binding, thought to be of a non-specific lipophilic nature, has not yet been investigated. The aim of this study was to determine the differential pattern of AV-45 binding in white matter in healthy and pathological populations. METHODS: We recruited 24 patients presenting with AD at an early stage and 17 matched, healthy subjects. We used an optimized positron emission tomography-magnetic resonance imaging (PET-MRI) registration method and an approach based on an intensity histogram using several indices. We compared the results of the intensity histogram analyses with a more canonical approach based on target-to-cerebellum Standard Uptake Value (SUVr) in white and grey matter using MANOVA and discriminant analyses. A cluster analysis on white and grey matter histograms was also performed. RESULTS: White matter histogram analysis revealed significant differences between AD and healthy subjects, which were not revealed by SUVr analysis. However, white matter histograms were not decisive to discriminate groups, and indices based on grey matter only showed better discriminative power than SUVr. The cluster analysis divided our sample into two clusters, showing different uptakes in grey, but also in white matter. CONCLUSION: These results demonstrate that AV-45 binding in white matter conveys subtle information not detectable using the SUVr approach. Although it is not more efficient than standard SUVr in discriminating AD patients from healthy subjects, this information could reveal white matter modifications.