Andrea Varrone

European multicentre database of healthy controls for [123I]FP-CIT SPECT (ENC-DAT): age-related effects, gender differences and evaluation of different methods of analysis

PurposeDopamine transporter (DAT) imaging with [123I]FP-CIT (DaTSCAN) is an established diagnostic tool in parkinsonism and dementia. Although qualitative assessment criteria are available, DAT quantification is important for research and for completion of a diagnostic evaluation. One critical aspect of quantification is the availability of normative data, considering possible age and gender effects on DAT availability. The aim of the European Normal Control Database of DaTSCAN (ENC-DAT) study was to generate a large database of [123I]FP-CIT SPECT scans in healthy controls.MethodsSPECT data from 139 healthy controls (74 men, 65 women; age range 20u2009–u200983xa0years, mean 53xa0years) acquired in 13 different centres were included. Images were reconstructed using the ordered-subset expectation-maximization algorithm without correction (NOACSC), with attenuation correction (AC), and with both attenuation and scatter correction using the triple-energy window method (ACSC). Region-of-interest analysis was performed using the BRASS software (caudate and putamen), and the Southampton method (striatum). The outcome measure was the specific binding ratio (SBR).ResultsA significant effect of age on SBR was found for all data. Gender had a significant effect on SBR in the caudate and putamen for the NOACSC and AC data, and only in the left caudate for the ACSC data (BRASS method). Significant effects of age and gender on striatal SBR were observed for all data analysed with the Southampton method. Overall, there was a significant age-related decline in SBR of between 4xa0% and 6.7xa0% per decade.ConclusionThis study provides a large database of [123I]FP-CIT SPECT scans in healthy controls across a wide age range and with balanced gender representation. Higher DAT availability was found in women than in men. An average age-related decline in DAT availability of 5.5xa0% per decade was found for both genders, in agreement with previous reports. The data collected in this study may serve as a reference database for nuclear medicine centres and for clinical trials using [123I]FP-CIT SPECT as the imaging marker.

Quantitative analysis of [11C]AZ10419369 binding to 5-HT1B receptors in human brain

A novel radioligand for positron emission tomography (PET) imaging of serotonin 5-HT1B receptors, [11C]AZ10419369, has been recently described. In this study, the potential for quantitative analysis of [11C]AZ10419369 binding to central 5-HT1B receptors was evaluated in human subjects. PET measurements were performed after injection of [11C]AZ10419369 in 10 subjects. Data were analyzed with kinetic modeling and linear graphical analysis using the arterial plasma as input function, and with reference tissue models using cerebellar cortex as the reference region. Binding of [11C]AZ10419369 was highest in pallidum, ventral striatum, and occipital cortex and lowest in cerebellum. The percentage of unchanged radioligand in plasma was 97% to 99%, indicating that no significant amounts of radioactive metabolites were formed during the time of analysis. Time–activity curves of [11C]AZ10419369 could be described with both one-tissue compartment (1-TC) and two-tissue compartment (2-TC) models in the majority of subjects. The 2-TC model failed to deliver reasonable estimates of the kinetic parameters. However, stable estimates of binding potential (BPND) were obtained by constraining K1/k2 to the distribution volume obtained with the 1-TC model in the cerebellar cortex. BPND values estimated with reference tissue models were correlated with the corresponding values obtained with kinetic modeling. The findings support the use of reference tissue models in applied clinical studies with [11C]AZ10419369.

Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients.

BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinsons disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 μg rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD. TRIAL REGISTRATION. Clinical Trials.gov NCT00866502. FUNDING. Newron Sweden AB (former NeuroNova AB) and Swedish Governmental Agency for Innovation Systems (VINNOVA).

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

PurposeApart from binding to the dopamine transporter (DAT), [123I]FP-CIT shows moderate affinity for the serotonin transporter (SERT), allowing imaging of both monoamine transporters in a single imaging session in different brain areas. The aim of this study was to systematically evaluate extrastriatal binding (predominantly due to SERT) and its age and gender dependencies in a large cohort of healthy controls.MethodsSPECT data from 103 healthy controls with well-defined criteria of normality acquired at 13 different imaging centres were analysed for extrastriatal binding using volumes of interest analysis for the thalamus and the pons. Data were examined for gender and age effects as well as for potential influence of striatal DAT radiotracer binding.ResultsThalamic binding was significantly higher than pons binding. Partial correlations showed an influence of putaminal DAT binding on measured binding in the thalamus but not on the pons. Data showed high interindividual variation in extrastriatal binding. Significant gender effects with 31xa0% higher binding in women than in men were observed in the thalamus, but not in the pons. An age dependency with a decline per decade (±standard error) of 8.2u2009±u20091.3xa0% for the thalamus and 6.8u2009±u20092.9xa0% for the pons was shown.ConclusionThe potential to evaluate extrastriatal predominant SERT binding in addition to the striatal DAT in a single imaging session was shown using a large database of [123I]FP-CIT scans in healthy controls. For both the thalamus and the pons, an age-related decline in radiotracer binding was observed. Gender effects were demonstrated for binding in the thalamus only. As a potential clinical application, the data could be used as a reference to estimate SERT occupancy in addition to nigrostriatal integrity when using [123I]FP-CIT for DAT imaging in patients treated with selective serotonin reuptake inhibitors.

Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington’s Disease Models

Huntingtons disease (HD) symptoms are driven to axa0large extent by dysfunction of the basal ganglia circuitry. HD patients exhibit reduced striatal phoshodiesterase 10 (PDE10) levels. Using HD mouse models that exhibit reduced PDE10, we demonstratexa0the benefit of pharmacologic PDE10 inhibition toxa0acutely correct basal ganglia circuitry deficits. PDE10 inhibition restored corticostriatal input and boosted cortically driven indirect pathway activity. Cyclic nucleotide signaling is impaired in HD models, and PDE10 loss may represent a homeostatic adaptation to maintain signaling. Elevation of both cAMP and cGMP by PDE10 inhibition was required for rescue. Phosphoproteomic profiling of striatum in response to PDE10 inhibition highlighted plausible neural substrates responsible for the improvement. Early chronic PDE10 inhibition in Q175 mice showed improvements beyond those seen with acute administration after symptom onset, including partial reversal of striatal deregulated transcripts and the prevention of the emergence of HD neurophysiological deficits. VIDEO ABSTRACT.

No difference in striatal dopamine transporter availability between active smokers, ex-smokers and non-smokers using [123I]FP-CIT (DaTSCAN) and SPECT

BackgroundMesolimbic and nigrostriatal dopaminergic pathways play important roles in both the rewarding and conditioning effects of drugs. The dopamine transporter (DAT) is of central importance in regulating dopaminergic neurotransmission and in particular in activating the striatal D2-like receptors. Molecular imaging studies of the relationship between DAT availability/dopamine synthesis capacity and active cigarette smoking have shown conflicting results. Through the collaboration between 13 SPECT centres located in 10 different European countries, a database of FP-CIT-binding in healthy controls was established. We used the database to test the hypothesis that striatal DAT availability is changed in active smokers compared to non-smokers and ex-smokers.MethodsA total of 129 healthy volunteers were included. Subjects were divided into three categories according to past and present tobacco smoking: (1) non-smokers (n = 64), (2) ex-smokers (n = 39) and (3) active smokers (n = 26). For imaging of the DAT availability, we used [123I]FP-CIT (DaTSCAN) and single photon emission computed tomography (SPECT). Data were collected in collaboration between 13 SPECT centres located in 10 different European countries. The striatal measure of DAT availability was analyzed in a multiple regression model with age, SPECT centre and smoking as predictor.ResultsThere was no statistically significant difference in DAT availability between the groups of active smokers, ex-smokers and non-smokers (p = 0.34). Further, we could not demonstrate a significant association between striatal DAT and the number of cigarettes per day or total lifetime cigarette packages in smokers and ex-smokers.ConclusionOur results do not support the hypothesis that large differences in striatal DAT availability are present in smokers compared to ex-smokers and healthy volunteers with no history of smoking.

Positron emission tomography imaging of 5-hydroxytryptamine1B receptors in Parkinson's disease

Impairment of the central serotonin system in Parkinsons disease (PD) has been shown postmortem and in vivo with positron emission tomography (PET). The aim of this PET study was to examine and compare the availability of the 5-hydroxytryptamine (5-HT)(1B)-receptor subtype in patients with PD and age-matched control subjects. Twelve control subjects and 12 PD patients were examined with PET using the 5-HT(1B)-radioligand [(11)C]AZ10419369. In PD patients, 5-HT(1B)-receptor availability in the right orbitofrontal cortex was lower than in control subjects. A statistically significant negative correlation between 5-HT(1B)-receptor availability and age was obtained for the right temporal cortex in control subjects and for the right midbrain and left parahippocampal gyrus in PD patients. The lower regional 5-HT(1B)-receptor availability is in line with previous studies showing a decrease of serotonin imaging markers in PD and corroborates a role of the serotonin system in the pathophysiology of PD. The demonstrated age effect on 5-HT(1B) receptors suggest a physiologic and PD-related decline of serotonin function, indicating the importance of controlling for age in clinical studies.

Reduction in camera-specific variability in [ 123 I]FP-CIT SPECT outcome measures by image reconstruction optimized for multisite settings: impact on age-dependence of the specific binding ratio in the ENC-DAT database of healthy controls

PurposeQuantitative estimates of dopamine transporter availability, determined with [123I]FP-CIT SPECT, depend on the SPECT equipment, including both hardware and (reconstruction) software, which limits their use in multicentre research and clinical routine. This study tested a dedicated reconstruction algorithm for its ability to reduce camera-specific intersubject variability in [123I]FP-CIT SPECT. The secondary aim was to evaluate binding in whole brain (excluding striatum) as a reference for quantitative analysis.MethodsOf 73 healthy subjects from the European Normal Control Database of [123I]FP-CIT recruited at six centres, 70 aged between 20 and 82xa0years were included. SPECT images were reconstructed using the QSPECT software package which provides fully automated detection of the outer contour of the head, camera-specific correction for scatter and septal penetration by transmission-dependent convolution subtraction, iterative OSEM reconstruction including attenuation correction, and camera-specific “to kBq/ml” calibration. LINK and HERMES reconstruction were used for head-to-head comparison. The specific striatal [123I]FP-CIT binding ratio (SBR) was computed using the Southampton method with binding in the whole brain, occipital cortex or cerebellum as the reference. The correlation between SBR and age was used as the primary quality measure.ResultsThe fraction of SBR variability explained by age was highest (1) with QSPECT, independently of the reference region, and (2) with whole brain as the reference, independently of the reconstruction algorithm.ConclusionQSPECT reconstruction appears to be useful for reduction of camera-specific intersubject variability of [123I]FP-CIT SPECT in multisite and single-site multicamera settings. Whole brain excluding striatal binding as the reference provides more stable quantitative estimates than occipital or cerebellar binding.

5‐HT1B receptor imaging and cognition: A positron emission tomography study in control subjects and parkinson's disease patients

The serotonin 5‐HT1B receptor subtype is involved in the modulation of serotonin release and is a target of interest for neuroreceptor imaging. Previous studies have shown that the serotonin system is affected in Parkinsons disease (PD). Cognitive function, frequently impaired in PD, has been linked to the serotonin system. The aim of this study was to examine whether 5‐HT1B receptor availability in the brain of healthy subjects and PD patients is associated with measures of cognitive function.

Distinct regional age effects on [11C]AZ10419369 binding to 5-HT1B receptors in the human brain

PURPOSEnAge-related changes in the serotonin system have been described, and proposed to be associated with behavioral changes observed particularly in the elderly population. The 5-HT1B receptor is thought to have a regulatory role in a number of physiological functions, and has been implicated in several age-related diseases. The purpose of the present study was to examine if the availability of 5-HT1B receptors is decreasing with age in healthy subjects.nnnMETHODSnData from five previous studies were reanalyzed and pooled, generating data from fifty-one healthy subjects, age 20 to 70, that had been examined with positron emission tomography (PET) and the 5-HT1B specific radioligand [11C]AZ10419369 at baseline conditions. The binding potential (BPND) in cortical and subcortical areas was calculated using the simplified reference tissue model (SRTM). After correction for partial volume effects (PVEc), the correlation between age and regional BPND was examined.nnnRESULTSnA statistically significant negative correlation between age and BPND was obtained for neocortical regions and the ventral striatum (VST). The average reduction in BPND per decade was 8% in cortex and 4% in VST. The BPND in the caudate nucleus and the putamen was mainly unaffected by age.nnnCONCLUSIONnThe 5-HT1B receptor availability decreases by age in cortical regions, whereas it remains stable in the caudate nucleus and putamen. By consequence, age-matching of control subjects will be necessary in future clinical studies.