Joachim Mazère

Comparison of Noninvasive Quantification Methods of in Vivo Vesicular Acetylcholine Transporter Using [123I]-IBVM SPECT Imaging

Dementia with Lewy Body and Alzheimers disease exhibit degeneration of the cholinergic neurons, and currently, the primary target of treatment is the cholinergic neurotransmitter system. [123I]-IBVM is a highly selective radioligand for in vivo visualization of the vesicular acetylcholine transporter (VAChT) using single photon emission computed tomography. This study compares different noninvasive methods using the occipital cortex as a reference region for the quantification of [123l]-IBVM binding in six older, healthy volunteers: two kinetic analyses based on one-tissue (1TCM) or two-tissue compartment model (2TCM), one linear and one multilinear analysis, and a simplified peak equilibrium analysis. Time—activity curves were well described by a 1TCM for all regions. The 2TCM converged reliably only in the striatum. Goodness of fit was not improved by using a 2TCM as compared with a 1TCM. The multilinear analysis gave binding potentials similar to the 1TCM while being more robust. The peak equilibrium method might prove to be a useful simplified analysis. The binding potentials obtained with reference region methods strongly correlated with results from invasive blood-sampling analysis. Noninvasive quantification of [123I]-IBVM data provides reliable estimates of VAChT binding, which is most valuable to study neurodegenerative diseases with specific cholinergic alteration.

Progressive Supranuclear Palsy: In Vivo SPECT Imaging of Presynaptic Vesicular Acetylcholine Transporter with [123I]-Iodobenzovesamicol

PURPOSE To evaluate the integrity of brain cholinergic pathways in vivo in patients with progressive supranuclear palsy (PSP) by measuring the vesicular acetylcholine transporter expression at single photon emission computed tomography (SPECT) with [123I]-iodobenzovesamicol. MATERIALS AND METHODS All participants provided informed written consent according to institutional human ethics committee guidelines. Ten patients with PSP and 12 healthy volunteers underwent dynamic [123I]-iodobenzovesamicol SPECT and magnetic resonance (MR) imaging. CT and MR images were used to register the dynamic SPECT image to the Montreal Neurologic Institute brain template, which includes the regions of interest of the striatum and the septo-hippocampal, innominato-cortical, and ponto-thalamic cholinergic pathways. For each region of interest, pharmacokinetic modeling of regional time activity curves was used to calculate [123I]-iodobenzovesamicol to vesicular acetylcholine transporter binding potential value, proportional to vesicular acetylcholine transporter expression. RESULTS When compared with control participants, patients with PSP had binding potential values that were unchanged in the striatum and septohippocampal pathway, significantly lower in the anterior cingulate cortex (P=.017) in the innominatocortical pathway, and significantly decreased in the thalamus (P=.014) in the pontothalamic cholinergic pathway. In addition, binding potential values in the thalamus were positively correlated with those in the pedunculopontine nucleus (ρ=0.81, P<.004) and binding potential values in both the thalamus (ρ=-0.88, P<.001) and pedunculopontine nucleus (ρ=-0.80, P<.010) were inversely correlated with disease duration. CONCLUSION Cholinergic pathways were differentially affected in the PSP group, with a significant alteration of pontothalamic pathways that increased with disease progression at both cell body and terminal levels, while the innominatocortical pathway was only mildly affected, and the septohippocampal pathway and the striatum were both preserved.

123I-iodobenzovesamicol SPECT Imaging of Cholinergic Systems in Dementia with Lewy Bodies

Cholinergic alterations in dementia with Lewy bodies (DLB) have been widely documented in postmortem studies, whereas in vivo studies are sparse, particularly at the subcortical level. We used 123I-iodobenzovesamicol, a SPECT radiotracer of the vesicular acetylcholine transporter, to evaluate in vivo in DLB the integrity of the 3 main cholinergic pathways—the Ch1 (septohippocampal), the Ch4 (innominatocortical), and the Ch5 (pontothalamic) cholinergic pathways—as well as the striatal cholinergic interneurons. In addition, we assessed the involvement of the cholinergic system in cognitive and neuropsychiatric disorders in DLB patients. Methods: Twelve healthy volunteers (median age, 72 y; interquartile range, 6.25 y) and 11 DLB patients (median age, 76 y; interquartile range, 10.50 y) underwent a dynamic 123I-iodobenzovesamicol SPECT scan and an MRI scan. MR images were automatically segmented, providing the volumes of several regions of interest, including the striatum and cholinergic terminals in Ch1 (hippocampus), Ch4 (cortical lobes), and Ch5 (thalamus). For each region of interest and each subject, pharmacokinetic modeling allowed calculation of the nondisplaceable binding potential (BPND) values for the binding of 123I-iodobenzovesamicol to the vesicular acetylcholine transporter. A neuropsychological evaluation of participants was performed with the Mini-Mental State Examination and the Grober–Buschke, Set, visual discrimination, Benton, and Wechsler tests, and cognitive fluctuations and apathy were also assessed. Results: Compared with BPND values for healthy subjects, BPND values for DLB patients were significantly lower in the Ch4 terminal regions of the anterior cingulate cortex and the superior and inferior parietal cortices (P = 0.0006, 0.0015, and 0.0023, respectively), in the Ch5 terminal region of the thalamus (P = 0.0003), and in the striatum (P = 0.0042). All of the neuropsychological test scores were significantly lower in DLB patients than in healthy subjects. Four DLB patients with apathy and 4 DLB patients without apathy were identified. For the anterior cingulate cortex, compared with BPND values in healthy subjects, BPND values were significantly lower in patients with apathy (P = 0.004) and were unchanged in patients without apathy. Conclusion: Our results confirm the existence in DLB of cholinergic alterations, reaching both cortical and subcortical levels, including the Ch5 pathway and the striatum. Alterations in cholinergic transmission in the anterior cingulate cortex could be closely associated with the development of apathy.

A phantom-based method to standardize dose-calibrators for new β+-emitters.

Quantitative imaging with PET requires accurate measurements of the amount of radioactivity injected into the patient and the concentration of radioactivity in a given region. Recently, new positron emitters, such as 124I, 89Zr, 82Rb, 68Ga, and 64Cu, have emerged to promote PET development, but standards are still largely lacking. Therefore, we propose to validate a simple, robust, and replicable methodology, not requiring the use of any standards, to accurately calibrate a dose-calibrator for any &bgr;+-emitter. On the basis of 18F cross-calibration, routinely performed with fluorine-18-fluorodeoxyglucose (18F-FDG) in nuclear medicine departments, a methodology was developed using &bgr;+-emitting’ phantoms to cross-calibrate the dose-calibrator for measuring the activity of positron emitters and quantifying the standardized uptake value (SUV). 68Ga phantoms filled with activities measured with various dose-calibrator settings were imaged to establish calibration curves (SUV values as a function of the dose-calibrator settings) and to identify the setting value, yielding an SUV value of 1.00 g/ml, reflecting an accurate measurement of 68Ga activity. Activities measured with the identified setting were finally checked with a &ggr;-counter. The setting of 772±1 was identified as ensuring that the studied dose-calibrator is correctly calibrated for 68Ga to ensure an SUV value of 1.00±0.01 g/ml. &ggr;-Ray spectrometry confirmed the accurate measurement of 68Ga activities by the dose-calibrator (relative error of 2.9±1.5%). We have developed a phantom-based method to accurately standardize dose-calibrators for any &bgr;+-emitter, without any standards.

Adverse Reactions to Radiopharmaceuticals in France Analysis of the National Pharmacovigilance Database

Background: Radiopharmaceuticals are regarded as safe by the nuclear medicine community, but up to now, no survey has been conducted with from the perspective of pharmacovigilance. Objective: To describe the adverse reactions to radiopharmaceuticals (ARRPs) reported to the French Pharmacovigilance Database (FPVD). Methods: We selected and described all reports encompassing at least one radiopharmaceutical in the FPVD. The annual incidence of reported ARRPs used in diagnosis was also estimated. Results: From 1989 to 2013, 304 reports of ARRPs were identified (43.0% serious, 12 deaths) in 54.6% women and 45.4% men; the median age was 58 years. Five therapeutic radiopharmaceuticals (131I-sodium iodide, 131I-lipiodol, 89Sr-chloride, 153Sm-lexidronam, and 90Y-ibritumomab-tiuxetan) were involved in 48 reports (97 adverse reactions: 86.6% serious, 9 deaths). Pulmonary disorders represented 44.3% of ARRPs used for therapy, mainly related to 131I-lipiodol. There were 34 diagnostic radiopharmaceuticals involved in 256 reports (451 adverse reactions: 38.1% serious, 3 deaths); 8 diagnostic products (99mTc-oxidronate, 18F-fluorodeoxyglucose, 99mTc-tin pyrophosphate, 99mTc-tetrofosmin, 99mTc-dimercaptosuccinic acid, 201Tl-chloride, 99mTc-sestamibi, and 111In-pentetate) accounted for two-thirds of ARRPs. The most frequent adverse reactions were skin (34.4%), general (18.2%), nervous (9.0%), and gastrointestinal disorders (7.0%). There were 25 cases of altered images and 10 medication errors. The annual incidence of reported adverse reactions ranged from 1.2 × 10−5 to 3.4 × 10−5 diagnostic administrations. Conclusions: Reported ARRPs occurred rarely and were more serious in the therapeutic than in the diagnostic field. The notification of ARRPs was able to provide new guidance for safe use, as was the case for 131I-lipiodol. Therefore, it is important to report ARRPs to a pharmacovigilance system.

Cholinergic impairment in Parkinson Plus Syndrome: A molecular imaging study

enriched tau proteins from the control and transgenic mice were immunoprecipitated with a monoclonal antibody against tau. The immuno-precipitants were then digested with trypsin. The phosphorylated peptides in the control and transgenic mouse samples were enriched once again by the CHT-based method. The phosphopeptides were then analyzed by MALDI-TOF mass spectrometry and the peptide mass profiles of tau protein were compared between the age-matched wild type and transgenic animals to examine the changes in tau protein phosphorylation. Conclusions: Our study demonstrated that CHT-based fractionation is an easy-to-use, fast and convenient method for phosphoprotein/peptide enrichment with high binding capacity. It could potentially be used to enrich highly-phophorylated proteins and facilitate the biochemical study of hyperphosphorylated tau in Alzheimer’s disease.

Simplified Quantification Method for In Vivo SPECT Imaging of the Vesicular Acetylcholine Transporter with 123I-Iodobenzovesamicol

123I-iodobenzovesamicol is a SPECT radioligand selective for the vesicular acetylcholine transporter (VAChT) and used to assess the integrity of cholinergic pathways in various neurologic disorders. The current noninvasive method for quantitative analysis of 123I-iodobenzovesamicol, based on multilinear reference tissue model 2 (MRTM2), requires repeated scans for several hours, limiting its application in clinical trials. Our objective was to validate a simplified acquisition method based on a single 123I-iodobenzovesamicol static scan preserving the quantification accuracy. Three acquisition times were tested comparatively to a kinetic analysis using MRTM2. Methods: Six healthy volunteers underwent a dynamic SPECT acquisition comprising 14 frames over 28 h and an MR imaging scan. MR images were automatically segmented, providing the volumes of 19 regions of interest (ROIs). SPECT datasets were coregistered with MR images, and regional time–activity curves were derived. For each ROI, a complete MRTM2 pharmacokinetic analysis, using the cerebellar hemispheres as the reference region, led to the calculation of a 123I-iodobenzovesamicol-to-VAChT binding parameter, the nondisplaceable binding potential (BPND-MRTM2). A simplified analysis was also performed at 5, 8, and 28 h after injection, providing a simplified BPND, given as BPND-t = CROI − Ccerebellar hemispheres/Ccerebellar hemispheres, with C being the averaged radioactive concentration. Results: No significant difference was found among BPND-5 h, BPND-8 h, and BPND-MRTM2 in any of the extrastriatal regions explored. BPND-28 h was significantly higher than BPND-5 h, BPND-8 h, and BPND-MRTM2 in 9 of the 17 regions explored (P < 0.05). BPND-5 h, BPND-8 h, and BPND-28 h correlated significantly with BPND-MRTM2 (P < 0.05; ρ = 0.99, 0.98, and 0.92, respectively). In the striatum, BPND-28 h was significantly higher than BPND-5 h and BPND-8 h. BPND-5 h differed significantly from BPND-MRTM2 (P < 0.05), with BPND-5 h being 43.6% lower. Conclusion: In the extrastriatal regions, a single acquisition at 5 or 8 h after injection provides quantitative results similar to a pharmacokinetic analysis. However, with the highest correlation and accuracy, 5 h is the most suitable time to perform an accurate 123I-iodobenzovesamicol quantification. In the striatum, none of the 3 times has led to an accurate quantification.