Dr Lauriane Jugé

PUBLICATIONS

Covertly active and progressing neurochemical abnormalities in suppressed HIV infection.

Cysique LA, Jugé L, Gates T, Tobia M, Moffat K, Brew BJ, Rae C

To assess whether HIV-related brain injury is progressive in persons with suppressed HIV infection. Our study reveals covertly active or progressing HIV-related brain injury in the majority of this virally suppressed cohort, reflecting ongoing neuropathogenic processes that are only partially worsened by historical HAND and HIV duration. Longer-term studies will be important for determining the prognosis of these slowly evolving neurochemical abnormalities.

Covertly active and progressing neurochemical abnormalities in suppressed HIV infection.

Cysique LA, Jugé L, Gates T, Tobia M, Moffat K, Brew BJ, Rae C

To assess whether HIV-related brain injury is progressive in persons with suppressed HIV infection. Our study reveals covertly active or progressing HIV-related brain injury in the majority of this virally suppressed cohort, reflecting ongoing neuropathogenic processes that are only partially worsened by historical HAND and HIV duration. Longer-term studies will be important for determining the prognosis of these slowly evolving neurochemical abnormalities.

Development of acute hydrocephalus does not change brain tissue mechanical properties in adult rats, but in juvenile rats.

Pong AC, Jugé L, Bilston LE, Cheng S

This study showed that although brain tissue in the adult hydrocephalic rats was severely compressed, their brain tissue stiffness did not change significantly. These results are in contrast with our previous findings in juvenile hydrocephalic rats which had significantly less brain compression (as the brain circumference was able to stretch with the cranium due to the open skull sutures) and had a significant increase in caudate putamen stiffness. These results suggest that change in brain mechanical properties in hydrocephalus is complex and is not solely dependent on brain tissue deformation. Further studies on the interactions between brain tissue stiffness, deformation, tissue oedema and neural damage are necessary before MRE can be used as a tool to track changes in brain biomechanics in hydrocephalus.

Liver Stiffness Values Are Lower in Pediatric Subjects than in Adults and Increase with Age: A Multifrequency MR Elastography Study.

Etchell E, Jugé L, Hatt A, Sinkus R, Bilston LE

Purpose To determine if healthy hepatic mechanical properties differ between pediatric and adult subjects at magnetic resonance (MR) elastography. Materials and Methods Liver shear moduli in 24 healthy pediatric participants (13 children aged 5-14 years [seven boys, six girls] and 11 adolescents aged 15-18 years [six boys, five girls]) and 10 healthy adults (aged 22-36 years [five men, five women]) were obtained with 3-T MR elastography at 28, 56, and 84 Hz. Relationships between shear moduli and age were assessed with Spearman correlations. Differences between age groups were determined with one-way analysis of variance and Tukey multiple comparisons tests. Results Liver stiffness values (means ± standard deviations) were significantly lower in children and adolescents than in adults at 56 Hz (children, 2.2 kPa ± 0.3; adolescents, 2.2 kPa ± 0.2; adults, 2.6 kPa ± 0.3; analysis of variance, P = .009) and 84 Hz (children, 5.6 kPa ± 0.8; adolescents, 6.5 kPa ± 1.2; adults, 7.8 kPa ± 1.2; analysis of variance, P = .0003) but not at 28 Hz (children, 1.2 kPa ± 0.2; adolescents, 1.3 kPa ± 0.3; adults, 1.2 kPa ± 0.2; analysis of variance, P = .40). At 56 and 84 Hz, liver stiffness increased with age (Spearman correlation, r = 0.38 [P = .03] and r = 0.54 [P = .001], respectively). Stiffness varied less with frequency in children and adolescents than in adults (analysis of variance, P = .0009). No significant differences were found in shear moduli at 28, 56, or 84 Hz or frequency dependence between children and adolescents (P = .38, P = .99, P = .14, and P = .30, respectively, according to Tukey tests). Conclusion Liver stiffness values are lower and vary less with frequency in children and adolescents than in adults. Stiffness increases with age during normal development and approaches adult values during adolescence. Comparing pediatric liver stiffness to adult baseline values to detect pediatric liver mechanical abnormalities may not allow detection of mild disease and may lead to underestimation of severity. (©) RSNA, 2016 Online supplemental material is available for this article.

Longitudinal measurements of postnatal rat brain mechanical properties in-vivo.

Pong AC, Jugé L, Cheng S, Bilston LE

Information on pediatric brain tissue mechanical properties and, more pertinently, how they change during postnatal development remains scarce despite its importance to investigate mechanisms of neural injury. The aim of this study is to determine whether brain mechanical properties change in-vivo during early postnatal development in a rat model. Rat brain viscoelastic properties were measured longitudinally in ten healthy Sprague Dawley rats at five different time points from postnatal week one to week six using magnetic resonance elastography at 800Hz. Myelination and cell density were assessed histologically at the same time points to understand how the underlying tissue microstructure may be associated with changes in mechanical properties at different brain regions. Longitudinal changes in each variable were assessed using a generalized linear model with pairwise comparisons of means between weeks. The brain shear modulus in the cortical gray matter at postnatal week one was 6.3±0.4kPa, and increased significantly from week one to week two (pairwise comparison, p<0.01), remained stable from week two to week four and decreased significantly by week six (pairwise comparison, p<0.001). In the deep gray matter, brain tissue stiffness at postnatal week one was 6.1±2.0kPa, and increased significantly from one to week four (pairwise comparison, p<0.05) before decreasing significantly by week six (pairwise comparison, p<0.001). Stiffness changes were not directly correlated to histological observations. These data suggest that brain tissue shear modulus initially increases during a period equivalent to early childhood, and then decreases during a period equivalent to adolescence.

Changes in Rat Brain Tissue Microstructure and Stiffness during the Development of Experimental Obstructive Hydrocephalus.

Jugé L, Pong AC, Bongers A, Sinkus R, Bilston LE, Cheng S

Understanding neural injury in hydrocephalus and how the brain changes during the course of the disease in-vivo remain unclear. This study describes brain deformation, microstructural and mechanical properties changes during obstructive hydrocephalus development in a rat model using multimodal magnetic resonance (MR) imaging. Hydrocephalus was induced in eight Sprague-Dawley rats (4 weeks old) by injecting a kaolin suspension into the cisterna magna. Six sham-injected rats were used as controls. MR imaging (9.4T, Bruker) was performed 1 day before, and at 3, 7 and 16 days post injection. T2-weighted MR images were collected to quantify brain deformation. MR elastography was used to measure brain stiffness, and diffusion tensor imaging (DTI) was conducted to observe brain tissue microstructure. Results showed that the enlargement of the ventricular system was associated with a decrease in the cortical gray matter thickness and caudate-putamen cross-sectional area (P < 0.001, for both), an alteration of the corpus callosum and periventricular white matter microstructure (CC+PVWM) and rearrangement of the cortical gray matter microstructure (P < 0.001, for both), while compression without gross microstructural alteration was evident in the caudate-putamen and ventral internal capsule (P < 0.001, for both). During hydrocephalus development, increased space between the white matter tracts was observed in the CC+PVWM (P < 0.001), while a decrease in space was observed for the ventral internal capsule (P < 0.001). For the cortical gray matter, an increase in extracellular tissue water was significantly associated with a decrease in tissue stiffness (P = 0.001). To conclude, this study characterizes the temporal changes in tissue microstructure, water content and stiffness in different brain regions and their association with ventricular enlargement. In summary, whilst diffusion changes were larger and statistically significant for majority of the brain regions studied, the changes in mechanical properties were modest. Moreover, the effect of ventricular enlargement is not limited to the CC+PVWM and ventral internal capsule, the extent of microstructural changes vary between brain regions, and there is regional and temporal variation in brain tissue stiffness during hydrocephalus development.

Effect of endoscopic third ventriculostomy on cerebrospinal fluid pressure in the cerebral ventricles.

Farnoush A, Tan K, Juge L, Bilston LE, Cheng S

We aimed to show how endoscopic third ventriculostomy (ETV) treatment may affect cerebrospinal fluid (CSF) flow dynamics in hydrocephalus, with and without aqueductal stenosis. Hydrocephalus is a neurological disorder which is characterized by enlarged brain ventricles. The periodic motion of CSF flow as a function of the cardiac cycle was prescribed as the inlet boundary condition at the foramen of Monro, and ETV was modeled as a 5mm diameter hole in the anterior wall of the third ventricle. The results show that ETV reduces the pressure in the ventricles by nine-fold in the model with aqueductal stenosis, and three-fold in the model without aqueductal stenosis. More importantly, ETV changes the temporal characteristics of the CSF pressure waveform in the model without aqueductal stenosis, such that there is higher pressure in the ventricle during diastole. This study suggests that changes in the temporal characteristics of the CSF pressure waveform in the ventricles may be the reason why ETV treatment is not effective for hydrocephalus without aqueductal stenosis.

Microvasculature alters the dispersion properties of shear waves--a multi-frequency MR elastography study.

Jugé L, Petiet A, Lambert SA, Nicole P, Chatelin S, Vilgrain V, Van Beers BE, Bilston LE, Sinkus R

Magnetic Resonance Elastography (MRE) uses macroscopic shear wave propagation to quantify mechanical properties of soft tissues. Micro-obstacles are capable of affecting the macroscopic dispersion properties of shear waves. Since disease or therapy can change the mechanical integrity and organization of vascular structures, MRE should be able to sense these changes if blood vessels represent a source for wave scattering. To verify this, MRE was performed to quantify alteration of the shear wave speed cs due to the presence of vascular outgrowths using an aortic ring model. Eighteen fragments of rat aorta included in a Matrigel matrix (n=6 without outgrowths, n=6 with a radial outgrowth extent of ~600 µm and n=6 with ~850 µm) were imaged using a 7 Tesla MR scanner (Bruker, PharmaScan). High resolution anatomical images were acquired in addition to multi-frequency MRE (ν = 100, 115, 125, 135 and 150 Hz). Average cs was measured within a ring of ~900 µm thickness encompassing the aorta and were normalized to cs0 of the corresponding Matrigel. The frequency dependence was fit to the power law model cs ~ν(y). After scanning, optical microscopy was performed to visualize outgrowths. Results demonstrated that in presence of vascular outgrowths (1) normalized cs significantly increased for the three highest frequencies (Kruskal-Wallis test, P = 0.0002 at 125 Hz and P = 0.002 at 135 Hz and P = 0.003 at 150 Hz) but not for the two lowest (Kruskal-Wallis test, P = 0.63 at 100 Hz and P = 0.87 at 115 Hz), and (2) normalized cs followed a power law behavior not seen in absence of vascular outgrowths (ANOVA test, P < 0.0001). These results showed that vascular outgrowths acted as micro-obstacles altering the dispersion relationships of propagating shear waves and that MRE could provide valuable information about microvascular changes.

Characterising skeletal muscle under large strain using eccentric and Fourier Transform-rheology.

Tan K, Cheng S, Jugé L, Bilston LE

Characterising the passive anisotropic properties of soft tissues has been largely limited to the linear viscoelastic regime and shear loading is rarely done in the large deformation regime, despite the physiological significance of such properties. This paper demonstrates the use of eccentric rheology, which allows the anisotropy of skeletal muscle to be investigated. The large amplitude oscillatory strain properties of skeletal muscle were also investigated using Fourier Transform-rheology. Histology was used to qualitatively assess the microstructure changes induced by large strain. Results showed that skeletal muscle was strongly anisotropic in the linear regime. The storage and loss moduli were found to be significantly different (p<0.05) between the three fibre alignment groups; for the group tested with fibres perpendicular to plane of shear was 12.3±1.3 kPa and 3.0±0.35 kPa, parallel to shear direction was 10.6±1.2 kPa and 2.4±0.23 kPa, and perpendicular to shear direction was 5.5±0.90 kPa and 1.3±0.21 kPa. The appearance and growth of higher order harmonics at large strain was different in the three testing directions indicating that the anisotropy of muscle affects skeletal muscle behaviour in the nonlinear regime. Histological analysis showed an increasing destruction of extracellular matrix and the rearrangement of fibres with increasing strain indicating mechanical damage at strains of larger than 10%. These microstructural changes could contribute to the complex nonlinear behaviour in skeletal muscle. This paper demonstrates a method of characterising the anisotropic properties in skeletal muscle under large strain whilst giving meaningful information on the physical response of tissue at various strains.

Bridging Three Orders of Magnitude: Multiple Scattered Waves Sense Fractal Microscopic Structures via Dispersion.

Lambert SA, Näsholm SP, Nordsletten D, Michler C, Juge L, Serfaty JM, Bilston L, Guzina B, Holm S, Sinkus R

Wave scattering provides profound insight into the structure of matter. Typically, the ability to sense microstructure is determined by the ratio of scatterer size to probing wavelength. Here, we address the question of whether macroscopic waves can report back the presence and distribution of microscopic scatterers despite several orders of magnitude difference in scale between wavelength and scatterer size. In our analysis, monosized hard scatterers 5  μm in radius are immersed in lossless gelatin phantoms to investigate the effect of multiple reflections on the propagation of shear waves with millimeter wavelength. Steady-state monochromatic waves are imaged in situ via magnetic resonance imaging, enabling quantification of the phase velocity at a voxel size big enough to contain thousands of individual scatterers, but small enough to resolve the wavelength. We show in theory, experiments, and simulations that the resulting coherent superposition of multiple reflections gives rise to power-law dispersion at the macroscopic scale if the scatterer distribution exhibits apparent fractality over an effective length scale that is comparable to the probing wavelength. Since apparent fractality is naturally present in any random medium, microstructure can thereby leave its fingerprint on the macroscopically quantifiable power-law exponent. Our results are generic to wave phenomena and carry great potential for sensing microstructure that exhibits intrinsic fractality, such as, for instance, vasculature.

In vivo anisotropic mechanical properties of dystrophic skeletal muscles measured by anisotropic MR elastographic imaging: the mdx mouse model of muscular dystrophy.

Qin EC, Jugé L, Lambert SA, Paradis V, Sinkus R, Bilston LE

The mechanical anisotropic ratio of the shear storage moduli measured by an anisotropic MR elastographic technique can distinguish between healthy muscle and dystrophic muscle.

Evaluation of Nonradiative Clinical Imaging Techniques for the Longitudinal Assessment of Tumour Growth in Murine CT26 Colon Carcinoma.

Seguin J, Doan BT, Latorre Ossa H, Jugé L, Gennisson JL, Tanter M, Scherman D, Chabot GG, Mignet N

Background and Objectives. To determine the most appropriate technique for tumour followup in experimental therapeutics, we compared ultrasound (US) and magnetic resonance imaging (MRI) to characterize ectopic and orthotopic colon carcinoma models. Methods. CT26 tumours were implanted subcutaneously (s.c.) in Balb/c mice for the ectopic model or into the caecum for the orthotopic model. Tumours were evaluated by histology, spectrofluorescence, MRI, and US. Results. Histology of CT26 tumour showed homogeneously dispersed cancer cells and blood vessels. The visualization of the vascular network using labelled albumin showed that CT26 tumours were highly vascularized and disorganized. MRI allowed high-resolution and accurate 3D tumour measurements and provided additional anatomical and functional information. Noninvasive US imaging allowed good delineation of tumours despite an hypoechogenic signal. Monitoring of tumour growth with US could be accomplished as early as 5 days after implantation with a shorter acquisition time (<5 min) compared to MRI. Conclusion. MRI and US afforded excellent noninvasive imaging techniques to accurately follow tumour growth of ectopic and orthotopic CT26 tumours. These two techniques can be appropriately used for tumour treatment followup, with a preference for US imaging, due to its short acquisition time and simplicity of use.

Characterising soft tissues under large amplitude oscillatory shear and combined loading.

Tan K, Cheng S, Jugé L, Bilston LE

Characterising soft biological tissues outside the linear viscoelastic regime is challenging due to their complex behaviour. In addition, the viscoelastic properties of tissues have been shown to be sensitive to sample preparation and loading regime resulting in inconsistent data varying by orders magnitude in the literature. This paper presents a novel technique to characterise the non-linear behaviour of tissues which uses Fourier Transformation to decompose the stress output waveform under large amplitude oscillatory shear (LAOS) into harmonic contributions. The effect of varying preload, the compressive strain exerted on a liver tissue specimen prior to shear testing to minimise slip, was also investigated. Results showed that in the linear regime, preload affects the viscoelastic response of liver. Histological analysis indicated that there were structural changes as a result of the preload that may be linked to the differences in observed behaviour. Fourier analysis was used to extract the first and third harmonic components of the shear moduli at large strain. At 50% shear strain, a change in the third harmonic component of the shear moduli was accompanied by a marked change in the micro-structural arrangement of the sinusoids. This paper demonstrates a method of efficiently characterising soft biological tissues under large amplitude oscillatory shear under combined loading.

Investigating relationship between transfection and permeabilization by the electric field and/or the Pluronic® L64 in vitro and in vivo.

Bureau MF, Wasungu L, Jugé L, Scherman D, Rols MP, Mignet N

A major finding of the present study is that the nature of the membrane modification induced by electric pulses is not comparable to that mediated by L64. The electrophoretic LV pulse does not induce additive effects to that of L64 for transfection improvement.

Colon tumor growth and antivascular treatment in mice: complementary assessment with MR elastography and diffusion-weighted MR imaging.

Jugé L, Doan BT, Seguin J, Albuquerque M, Larrat B, Mignet N, Chabot GG, Scherman D, Paradis V, Vilgrain V, Van Beers BE, Sinkus R

Imaging of mechanical properties and diffusivity provide complementary information during tumor growth and regression that are respectively linked to vascularity and tumor cell alterations, including cellularity and micronecrosis.

Muscle transfection and permeabilization induced by electrotransfer or pluronic L64: Paired study by optical imaging and MRI.

Bureau MF, Jugé L, Seguin J, Rager MN, Scherman D, Mignet N

Site-specific conjugation of metal carbonyl dendrimer to antibody and its use as detection reagent in immunoassay.

Fischer-Durand N, Salmain M, Rudolf B, Dai L, Jugé L, Guérineau V, Laprévote O, Vessières A, Jaouen G

We describe here the conjugation of polyclonal goat anti-rabbit antibody to generation 4 polyamidoamine (G4-PAMAM) dendrimers carrying (i) (η(5)-cyclopentadienyl) iron dicarbonyl succinimidato complexes as infrared (IR) probes, (ii) nitroaniline entities as nuclear magnetic resonance (NMR) probes, (iii) acetamide groups for surface neutralization, and (iv) hydrazide-terminated spacer arms for the reaction with aldehyde. To preserve a high binding affinity, the conjugation was performed on the carbohydrate moieties located on the Fc fragment. The resulting conjugates were characterized by Fourier transform-IR, ultraviolet (UV), and high-mass matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. On the basis of relative concentration ratios of IR probes and antibody, an average labeling of 30 IR probes per antibody was reached (i.e., more than twice the value obtained with our previous strategy that generated no spacer arm). Immunoassays revealed that the antibody-dendrimer conjugates retained 55.1% of immunoreactivity on average with respect to underivatized antibody. Finally, the conjugates were used to quantify their antigen by solid-phase carbonyl metallo immunoassay (CMIA). Results showed a significant enhancement of the IR signal, demonstrating the efficiency of the new conjugation strategy and the potential of the new antibody-dendrimer conjugates as universal immunoanalytical reagents.