Molecular imaging of microglial activation in amyotrophic lateral sclerosis.

There is growing evidence of activated microglia and inflammatory processes in the cerebral cortex in amyotrophic lateral sclerosis (ALS). Activated microglia is characterized by increased expression of the 18 kDa translocator protein (TSPO) in the brain and may be a useful biomarker of inflammation. In this study, we evaluated neuroinflammation in ALS patients using a radioligand of TSPO, (18)F-DPA-714. Ten patients with probable or definite ALS (all right-handed, without dementia, and untreated by riluzole or other medication that might bias the binding on the TSPO), were enrolled prospectively and eight healthy controls matched for age underwent a PET study. Comparison of the distribution volume ratios between both groups were performed using a Mann-Whitney's test. Significant increase of distribution of volume ratios values corresponding to microglial activation was found in the ALS sample in primary motor, supplementary motor and temporal cortex (p = 0.009, p = 0.001 and p = 0.004, respectively). These results suggested that the cortical uptake of (18)F-DPA-714 was increased in ALS patients during the "time of diagnosis" phase of the disease. This finding might improve our understanding of the pathophysiology of ALS and might be a surrogate marker of efficacy of treatment on microglial activation.

Initial evaluation in healthy humans of [18F]DPA-714, a potential PET biomarker for neuroinflammation.

INTRODUCTION: The translocator protein 18 kDa (TSPO), although minimally expressed in healthy brain, is up-regulated in pathological conditions, coinciding with microglial activation. It is thereby a suitable in vivo biomarker of neuroinflammation for detection, evaluation and therapeutic monitoring of brain diseases. We aimed to estimate the radiation dosimetry of the positron emission tomography (PET) TSPO radioligand [(18)F]DPA-714, and we evaluated in healthy volunteers its whole-body uptake and cerebral kinetics. METHODS: Biodistribution data from mice were used for the prediction of radiation dosimetry. In human studies, a 90-min dynamic PET scan was performed in seven healthy volunteers after injection of [(18)F]DPA-714 (245±45 MBq). Arterial and venous samples were collected from two subjects, and two additional subjects were submitted to whole-body acquisition. Regions of interest were defined over cerebral structures to obtain mean time-activity curves and to estimate the distribution volume ratios by Logan graphical analysis, and over peripheral organs to obtain standard uptake values. RESULTS: The effective dose estimated from biodistribution in mice was 17.2 µSv/MBq. Modeling of regional brain and plasma data showed good in vivo stability of [(18)F]DPA-714 in humans, with only 20% of blood metabolites 20 min postinjection (p.i.). Maximum cerebral uptake was observed 5 min p.i., followed by two decreasing phases: a rapid washout (5-30 min) followed by a slower phase for the remainder of PET acquisition. Whole-body images demonstrate high activity in the gallbladder, heart, spleen and kidneys. CONCLUSIONS: This initial study in humans shows that [(18)F]DPA-714 is a promising PET radioligand with excellent in vivo stability and biodistribution, and acceptable effective dose estimation. Therefore, [(18)F]DPA-714 could provide a sensitive measure of neuroinflammatory changes in subsequent clinical investigations.

Evaluation of a 3D local multiresolution algorithm for the correction of partial volume effects in positron emission tomography.

PURPOSE: Partial volume effects (PVEs) are consequences of the limited spatial resolution in emission tomography leading to underestimation of uptake in tissues of size similar to the point spread function (PSF) of the scanner as well as activity spillover between adjacent structures. Among PVE correction methodologies, a voxel-wise mutual multiresolution analysis (MMA) was recently introduced. MMA is based on the extraction and transformation of high resolution details from an anatomical image (MR/CT) and their subsequent incorporation into a low-resolution PET image using wavelet decompositions. Although this method allows creating PVE corrected images, it is based on a 2D global correlation model, which may introduce artifacts in regions where no significant correlation exists between anatomical and functional details. METHODS: A new model was designed to overcome these two issues (2D only and global correlation) using a 3D wavelet decomposition process combined with a local analysis. The algorithm was evaluated on synthetic, simulated and patient images, and its performance was compared to the original approach as well as the geometric transfer matrix (GTM) method. RESULTS: Quantitative performance was similar to the 2D global model and GTM in correlated cases. In cases where mismatches between anatomical and functional information were present, the new model outperformed the 2D global approach, avoiding artifacts and significantly improving quality of the corrected images and their quantitative accuracy. CONCLUSIONS: A new 3D local model was proposed for a voxel-wise PVE correction based on the original mutual multiresolution analysis approach. Its evaluation demonstrated an improved and more robust qualitative and quantitative accuracy compared to the original MMA methodology, particularly in the absence of full correlation between anatomical and functional information.

[Imaging and the new fabric of the human body]. / Représentation en sciences du vivant (2)--L'imagerie et la nouvelle "fabrique" du corps humain.

A short historical survey recalls the main techniques of medical imaging, based on modern physico-chemistry and computer science. Imagery has provided novel visions of the inside of the body, which are not self-obvious but require a training of the gaze. Yet, these new images have permeated the contemporary mind and inspired esthetic ventures. The popularity of these images may be related to their ambiguous status, between real and virtual. The images, reminiscent of Vesalius' De humani corporis fabrica, crosslink art, science and society in a specific way: which role will they play in the "empowerment" of the tomorrow patient?

[Lymphoscintigraphic exploration in the limbs lymphatic disease]. / Exploration lymphoscintigraphique dans la maladie lymphatique des membres.

Lymphoscintigraphy is based upon the physiological transport of small radioactive particles injected into interstitium toward lymphatic vessels and nodes. Lymphoscintigraphy directly investigates lymphatic system while other methods (ultrasounds, CT, MRI) investigate tissular consequences of lymphatic disease. The scintigraphic procedure has to be standardized in order to be reproducible. Lymphatic vessels, lymphatic nodes and interstitium are systematically analysed. Interpretation is visual and qualitative. Multiple abnormalities can be observed. However, none of them can consistently differentiate between primary and secondary lymphedema. Differential diagnosis is usually obtained by taking together clinical and lymphoscintigraphic data. By providing informations about lymphatic component and physiopathology of edema, lymphoscintigraphy contributes to the management of lymphedema. Hybrid imaging is a new imaging modality of edema. Recently used, it combines functional (scintigraphy) and anatomical (CT) data and seems to be able to provide further informations.

90Y-edotreotide for metastatic carcinoid refractory to octreotide.

PURPOSE: Metastatic carcinoid is an incurable malignancy whose symptoms, such as diarrhea and flushing, can be debilitating and occasionally life-threatening. Although symptom relief is available with octreotide, the disease eventually becomes refractory to octreotide, leaving no proven treatment options. The goal of this study was to evaluate the clinical effect of using (90)Y-edotreotide to treat symptomatic patients with carcinoid tumors. PATIENTS AND METHODS: Patients enrolled had metastatic carcinoid, at least one sign/symptom refractory to octreotide, and at least one measurable lesion. Study treatment consisted of three cycles of 4.4 GBq (120 mCi) (90)Y-edotreotide each, once every 6 weeks. RESULTS: Ninety patients were enrolled in the study. Using Southwest Oncology Group tumor response criteria, 67 (74.%) of 90 patients (95% CI, 65.4% to 83.4%) were objectively stable or responded. A statistically significant linear trend toward improvement was demonstrated across all 12 symptoms assessed. Median progression-free survival was significantly greater (P = .03) for the 38 patients who had durable diarrhea improvement than the 18 patients who did not (18.2 v 7.9 months, respectively). Adverse events (AEs) were reported in 96.7% (87 of 90) of patients. These AEs consisted primarily of reversible GI events (76 of 90), which could be caused in part by concomitant administration of amino acid solution given to reduce radiation exposure to the kidneys. There was one case each of grade 3 oliguria and grade 4 renal failure, each lasting 6 days. CONCLUSION: (90)Y-edotreotide treatment improved symptoms associated with malignant carcinoid among subjects with no treatment alternatives. Treatment was well-tolerated and had an acceptable expected AE profile.

Evaluation of a solid bolus suitable for esophageal scintigraphy.

This study was designed to select a suitable solid bolus for esophageal scintigraphy. Optimally, a bolus should leave minimal residual buccal and pharyngeal activity after being swallowed. We compared the oropharyngeal behavior of three boluses, i.e., omelette, egg white, and paté of 1- and 3-ml volume. Thirty patients without dysfunction of the upper esophageal sphincter were recruited for the study. Scintigraphy interpretation was based on the results of condensed images and time activity curves. A total of 108 oropharyngeal transits were analyzed. First we determined the most appropriate volume (1 or 3 ml) of paté, omelette, and egg white (i.e., the volume with the least residual oropharyngeal activity). Buccal or pharyngeal bolus retention occurred significantly less frequently with 1 ml paté than 3 ml (p = 0.03) and also less frequently with 3 ml egg white than with 1 ml egg white (p = 0.03), and the mean buccal bolus retention index was lower using 3 ml omelette than 1 ml omelette (p = 0.03). Then we identified the most suitable of the three selected boluses. Both oral and pharyngeal residues were higher for paté (1 ml) than for omelette (p = 0.02 and 0.05), and pharyngeal residue was significantly lower for omelette (3 ml) than for egg white (3 ml) (p = 0.02). In conclusion, a 3-ml bolus of radiolabeled omelette seems to be the most suitable bolus for exploration of esophageal transit, and its use could enhance the potential of scintigraphy in the assessment of esophageal disorders.

Presymptomatic diagnosis of experimental Parkinsonism with 123I-PE2I SPECT.

Presymptomatic diagnosis of the loss of nigrostriatal neurons that characterises Parkinson's disease, is a crucial issue for future neuroprotective therapies as degeneration exceeds 70 to 80% when symptoms appear. Here we propose an early diagnosis method that utilises single photon emission computerized tomography (SPECT) coupled to the iodine-123-labelled selective dopamine transporter ligand N-(3-ioprop-2E-enyl)-2-beta-(4-methylphenyl)nortropane ((123)I-PE2I), applying Logan's graphical method for quantification. Sequential (123)I-PE2I SPECT acquisitions were performed in nonhuman primates chronically treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine according to a regimen that consistently produces a progressive Parkinsonian state. While classical neurological examination only allows detection of Parkinsonian signs at Day 12 of the protocol of intoxication, the mean distribution volume ratio calculated according to Logan's graphical method is significantly decreased from Day 6 onward, i.e., when animals are clinically normal. (123)I-PE2I SPECT is a very sensitive method to detect presymptomatic lesions of nigrostriatal neurons and the first to be experimentally validated. It could now be used clinically for early diagnosis and follow-up of neuroprotective treatment.

Quantification of dopamine transporter by 123I-PE2I SPECT and the noninvasive Logan graphical method in Parkinson's disease.

UNLABELLED: (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4'-methyl-phenyl) nortropane (PE2I), a cocaine analog, is a new, highly specific tracer for imaging dopamine transporter labeled with (123)I for in vivo SPECT. Its reversible binding on dopamine transporter and its rapid kinetics allow quantification of its binding potential according to a 3-compartment model. For quantification of distribution volume of reversible tracer, Logan developed a noninvasive and graphical method that allows accurate estimation of binding potential. In this study, we performed (123)I-PE2I SPECT on healthy volunteers and patients with Parkinson's disease (PD) to validate the Logan graphical method for quantification of (123)I-PE2I binding and to analyze the relationship between (123)I-PE2I SPECT and clinical features of this frequent degenerative disease. METHODS: Eight PD patients (3 women, 5 men; mean age, 64 +/- 7.9 y; disease duration range, 1-8 y, Hoehn and Yahr stage range, 1-2.5) and 8 age-matched healthy volunteers (4 women, 4 men; mean age, 61.5 +/- 9.5 y) were included in 2 centers and studied with SPECT. Four sequential SPECT imaging sessions of 15-min duration were performed from 5 to 65 min after bolus injection of 140 +/- 30 MBq of (123)I-PE2I. RESULTS: The kinetics of PE2I in healthy volunteers and PD patients were rapid, and the Logan graphical method allowed quantification of distribution volume ratio (DVR) in the caudate nucleus and putamen. (123)I-PE2I striatal specific binding was significantly reduced in PD patients, compared with healthy volunteers, in the caudate and putamen. The decrease of DVR in the putamen was significantly and inversely correlated to disease duration and Hoehn and Yahr stage. In asymmetric PD patients, (123)I-PE2I uptake was significantly more reduced in the putamen contralateral to the side with predominant clinical symptoms. However, (123)I-PE2I uptake was also significantly reduced in the ipsilateral putamen, compared with that in healthy volunteers, suggesting that (123)I-PE2I SPECT can detect nigrostriatal degeneration before the appearance of clinical symptoms. CONCLUSION: Our data indicate that the Logan graphical method is accurate for noninvasive quantification of PE2I and that (123)I-PE2I SPECT is a useful quantitative method for accurate estimation of nigrostriatal dopaminergic nerve terminal degeneration. The close relationships between SPECT findings and clinical data suggest that this method is useful for objectively following the progression of PD and for assessing the effect of potential neuroprotective treatments. Finally, our findings suggest that (123)I-PE2I SPECT can be used for preclinical and early diagnosis of PD.