Jean-Marie Caillé

In vivo macrophage activity imaging in the central nervous system detected by magnetic resonance

Cell‐specific imaging has been proposed to increase the potential of magnetic resonance imaging (MRI) for tissue analysis. The hypothezis of the present work was that following intravenous injection of ultra‐small particle iron oxide, a contrast agent that accumulates in mononuclear phagocyte cells, macrophages with iron burden would be detectable by MRI within the central nervous system at sites of inflammatory cellular activity. In experimental autoimmune encephalomyelitis in Lewis rats (in which intense macrophage activity results from both hematogenous macrophages and activated microglia), lesions have been seen by MRI as low signal intensities related to magnetic susceptibility effects induced by iron particles. Electron microscopy has revealed the presence of such particles within the cytoplasm of cells that had the morphological aspect of macrophages. Macrophage activity imaging might increase MRI capability with regard to the in vivo pathophysiological aspects of central nervous system (CNS) diseases and might help in therapeutic trials in the numerous CNS diseases in which macrophages are involved. Magn Reson Med 41:329–333, 1999.

Early structural changes in acute MS lesions assessed by serial magnetization transfer studies

Background: Whether acute MS lesions are primarily inflammatory or demyelinative is unresolved. Our study examined acute MS lesions longitudinally by quantitative magnetization transfer (MT), an MRI technique that identifies tissue integrity and destruction. Methods: Four MS patients were studied by serial MRI including MT, conventional T2-weighted images, and postgadolinium T1-weighted images for 9 to 12 months. In 15 new lesions, the MT ratio (MTR) was calculated retrospectively. Results: In 13 lesions, a marked decrease in the MTR was present early during the first 2 months after the onset of the lesion and was followed by a variable increase. In two other lesions, the MTR progressively declined. Conclusions: These results suggest that major early structural changes compatible with demyelination and followed by remyelination and gliosis, or by continuous demyelination, occur in new MS lesions. The various MTR profiles provide in vivo confirmation of the current knowledge of the progression in MS lesions. Furthermore, MTR may be used to monitor in vivo drug efficacy in new MS lesions.

A functional magnetic resonance imaging study of mental subtraction in human subjects

The neuronal network involved in a precise type of calculation procedure, mental subtraction, was investigated by means of functional magnetic resonance imaging. Two tasks were used requiring covert production of numbers: (1) with calculation; (2) without calculation. During the first task, activation was observed in the left dorsolateral prefrontal and premotor cortices, in Brocas area and bilaterally in the inferior parietal cortex. During the second task, activation was mainly observed in Brocas area and to a less extent in the left prefrontal and premotor cortices. Statistical comparison of data in the two situations revealed that the procedure of mental subtraction is mediated by a distributed system which includes predominantly the left dorsolateral prefrontal cortex and the inferior parietal cortex bilaterally.

Dose and scanning delay using USPIO for central nervous system macrophage imaging.

Rationale and objectives: In experimental allergic encephalomyelitis (EAE), central nervous system (CNS) macrophage imaging is achievable by MRI using AMI-227 an ultra-small particle iron oxide contrast agent at a dose of 300 μmol/kg Fe. The objective was to test the feasibility at the human recommended dose of 45 μmol/kg Fe.Methods: Two groups of EAE rats were tested with AMI-227 using 45 and 300 μmol/kg Fe respectively. Following i.v. injection of AMI-227, they were scanned after a delay of 4–6 and 20–24 h.Results: With a high dose of AMI-227, all animals showed low signal intensity related to iron-loaded macrophages in the CNS. At low dose no abnormalities were found in the CNS. Furthermore, a delay of 4–6 h failed to demonstrate abnormalities even at high dose.Conclusions: Dose, scanning delay after administration and blood half-life are major parameters for T2* CNS macrophage imaging.

Early macrophage MRI of inflammatory lesions predicts lesion severity and disease development in relapsing EAE.

Magnetic resonance imaging (MRI) is of great utility in diagnosis and monitoring of multiple sclerosis (MS). Axonal loss is considered the main cause of accumulating irreversible disability. MRI using ultrasmall-super-paramagnetic-iron-oxide (USPIO) nanoparticles is a new technique to disclose in vivo central nervous system (CNS) inflammatory lesions infiltrated by macrophages in experimental autoimmune encephalomyelitis (EAE). Here, we raised the question of whether USPIO-enhanced MRI could serve as a tool to predict disease severity. We investigated, in a relapsing EAE model with various degrees of disease severity, the interindividual differences at the beginning of CNS inflammation as revealed in vivo by MRI with USPIO in correlation to the severity of both acute and chronic tissue damage including axonal loss. At the onset of the disease, observation of MRI alterations with USPIO allowed assignment of animals into USPIO+ and USPIO- groups. In 54.5% of diseased rats, MRI with USPIO+ at first attack revealed signal abnormalities mainly localized in the brainstem and cerebellum. Although animals did not present any clinically significant differences during the first attack, USPIO+ rats presented significantly more important tissue alterations at the first attack (onset and initiated recovery phase) and, at the second attack, more severe clinical disease with axonal loss compared to USPIO- rats. MRI lesion load and volume at the first attack correlate significantly with inflammation, macrophage recruitment, demyelination, acute axonal damage and, at the second attack, extent of axonal loss. This new MRI application of in vivo monitoring of macrophage infiltration provides a new platform to investigate the severity of inflammatory demyelinating CNS diseases.

RETRACTED: Influence of cognitive strategies on the pattern of cortical activation during mental subtraction. A functional imaging study in human subjects

Functional magnetic resonance imaging (fMRI) at 1.5 T was used to investigate the influence of cognitive strategies on cortical activation during mental calculation. Twenty-nine right-handed subjects performed a serial subtraction of prime numbers. Even though a common corpus of brain areas was activated during this mental calculation, differences appeared between subjects in function of their spontaneous cognitive strategy. In subjects using a so called verbal strategy (n=15), the main activation was located in the whole left dorsolateral frontal cortex with a little activation of the inferior parietal cortex. In subjects using a so called visual strategy (n=14), a bilateral activation in the prefrontal cortex and a high activation in the left inferior parietal cortex were observed. These results demonstrate that numbers are processed through a distributed network of cortical areas, the lateralization of which is clearly influenced by subject strategy.

Macrophage brain infiltration in experimental autoimmune encephalomyelitis is not completely compromised by suppressed T-cell invasion: in vivo magnetic resonance imaging illustration in effective anti-VLA-4 antibody treatment

Large inflammatory infiltrates of T cells, macrophages and B cells in the central nervous system (CNS) contribute to the pathogenesis of multiple sclerosis (MS). The passage of T cells through the blood-brain barrier can be suppressed with antibodies directed against alpha-4 integrins (VLA-4) that mediate T-cell adherence. This treatment, in phase III of clinical trial evaluation, reduces lesion development in MS patients. In the ongoing inflammatory disease process the consequences of T-cell inhibitory anti-VLA-4 antibodies on inflammatory compounds are still poorly investigated. We show that anti-VLA-4 antibody treatment during the late preclinical phase of the acute experimental autoimmune encephalomyelitis (EAE) MS rat model interrupts T-cell egress out of the vascular compartment and suppresses clinical disease and histological alterations but macrophage recruitment in the CNS is not fully compromised. Among the treated EAE animals not developing disease, none presented foci of T-cell infiltration in CNS. However, in 75% of the treated EAE rats monocyte ingress in CNS was observedin vivo by magnetic resonance imaging with the ultrasmall superparamagnetic iron oxide contrast agent. Our data shed new light on the role of remaining macrophage brain infiltration in an induced but interrupted T-cell-mediated EAE disease process.

Intraosseous lidocaine provides effective analgesia for percutaneous vertebroplasty of osteoporotic fractures

PurposeTo assess the safety and efficacy of intraosseous lidocaine (IL), in comparison with iv nalbuphine and propacetamol (NP) for analgesia during percutaneous vertebroplasty (PV) in order to avoid general anesthesia in elderly patients.MethodsPatients (age 68 ±13 yr, weight 66 ±6 kg) undergoing PV for osteoporotic fractures were randomized prospectively into two groups: NP(n = 50)and IL(n = 50). All patients were premedicated (oral hydroxyzine I mg·kg−1) and had skin infiltration with 5 ml_ of 1% lidocaine prior to vertebral puncture. Thirty minutes before the procedure, Group NP received, in a blinded manner, SO ml_ of iv nalbuphine (0.3 mg·kg−1) and propacetamol (30 mg·kg−1) while Group IL received 50 mL of iv saline. During vertebral puncture, Groups NP and IL received, in a blinded manner, I mL·10 kg−1 of intraosseous saline and 1% lidocaine respectively. Pain was assessed during vertebral puncture and cement injection with a four-point verbal rating scale. Additionally, lidocaine plasma kinetics were obtained in I I IL patients.ResultsAnalgesic efficacy was similar in the IL and NP groups (85 vs 84%). Group NP had more side effects. Lidocaine peak recorded concentration was 2.6 ±0.1 μg·mL−1 i.e., about three times less than the reported toxic limits.ConclusionIL is as effective as the association of iv NP for analgesia in PV. However, considering that both protocols were insufficient in about 15% of cases, other modalities are needed to further improve analgesia and avoid general anesthesia during vertebroplasty.RésuméObjectifÉvaluer l’efficacité et la sécurité d’une injection intraosseuse de lidocaïne (IL) comparée à une sédation iv à base de nalbuphine et de propacétamol (NP) pour l’analgésie des vertébroplasties percutanées (VP) afin d’éviter l’anesthésie générale chez des patients âgés.MéthodeCent patients devant subir une l’P sont prospectivement randomisés en deux groupes: 30 min avant la procédure, le groupe NP reçoit en aveugle 50 mL d’un mélange iv de nalbuphine (0,3 mg·kg−1) et de propacétamol (30 mg·kg−1) tandis que le groupe IL reçoit 50 mL iv de solution salée. Tous les patients reçoivent une prémédication avec de l’hydroxyzine (I mg·kg−1) et ont une infiltration cutanée avant la ponction vertébrale avec 5 mL de lidocaine I %. Pendant la ponction vertébrale, le groupe NP reçoit à son tour une solution salée alors que le groupe IL reçoit I mL· 10 kg−1 de lidocaïne I %. La douleur est évaluée pendant l’opération par une échelle verbale à quatre degrés. Un profil cinétique de la lidocaïne plasmatique est réalisé chez les 11 premiers patients.RésultatsUne analgésie efficace est constatée dans les groupes IL et NP dans 85 et 84 % des cas respectivement. Le groupe NP présente plus d’effets secondaires. Le pic plasmatique de lidocaïne circulante est 2,6 ±0,1 μg·mL−1 soit trois fois moins que les limites toxiques.ConclusionLa lidocaïne intra-osseuse procure la même analgésie que l’association iv de NP pour les l’P. Étant donné que les deux protocoles sont insuffisants dans environ 15% des cas, d’autres associations sont nécessaires pour améliorer encore l’analgésie et éviter l’anesthésie générale.

Correlation between Clinical Status and Macrophage Activity Imaging in the Central Nervous System of Rats

In both multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), macrophages are involved ubiquitously (a) to promote inflammation by interacting with other immune cells, (b) to attack the myelin sheath, and (c) to function as scavengers for myelin debris (1,2). In pathologic conditions, intrinsic central nervous system (CNS) cells called microglia are rapidly and intensively activated, and blood monocytes are recruited (1,2). We described a method to investigate in vivo by magnetic resonance imaging (MRI) the activity of macrophagic cells using ultrasmall superparamagnetic iron oxide (USPIO) (3–6). The USPIO particles accumulate in macrophages due to the affinity of iron for the C3 complement receptor. Their long relaxivities induce a T1 and a T2 shortening (7), detectable by MRI in the CNS of animals with EAE (4,6). Because macrophages are closely related to the activity of inflammatory and demyelinating diseases, we aimed this experimental study at evaluating the relationship between the clinical symptoms of EAE and the abnormalities seen by macrophage activity imaging (MAI). Groups of animals with EAE were clinically followed during the 28 days after inoculation, and MRI using USPIO was performed every day from day 3 to day 15 after inoculation.

Neuronal network inhibition following large noxious heat stimulation in humans

)werful inhibitions of dorsal horn neurons are triggered in animals by noxious stimulation of large cutaneous areas. This tenomenon described as “Diffuse Noxious Inhibitory Controls” (DNIC) involves supraspinal structures and can be observed, beit indirectly, in man. The question arises as to whether cortical network can be modified by the involvement of DNIC. The asent study was designed to examine the central effects of noxious heat applied to large areas, namely 560 (one hand) or 1120 n2 (two hands) using WRI.