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Background This prospective feasibility study explores Field-Cycling Imaging (FCI), a new MRI technology that measures the longitudinal relaxation time across a range of low magnetic field strengths, providing additional information about the molecular properties of tissues. This study aims to assess the performance of FCI and investigate new quantitative biomarkers at low fields within the context of breast cancer. Methods We conducted a study involving 9 people living with breast cancer (10 tumours in total, mean age, 54 ± 10 years). FCI images were obtained at four magnetic field strengths (2.3 mT to 200 mT). FCI images were processed to generate T1 maps and 1/T1 dispersion profiles from regions of tumour, normal adipose tissue, and glandular tissue. The dispersion profiles were subsequently fitted using a power law model. Statistical analysis focused on comparing potential FCI biomarkers using a Mann-Whitney U or Wilcoxon signed rank test. Results We show that low magnetic fields clearly differentiate tumours from adipose and glandular tissues without contrast agents, particularly at 22 mT (1/T 1 , median [IQR]: 6.8 [3.9–7.8] s −1 vs 9.1 [8.9–10.2] s −1 vs 8.1 [6.2–9.2] s −1 , P  < 0.01), where the tumour-to-background contrast ratio was highest (62%). Additionally, 1/T 1 dispersion indicated a potential to discriminate invasive from non-invasive cancers (median [IQR]: 0.05 [0.03–0.09] vs 0.19 [0.09–0.26], P  = 0.038). Conclusions To the best of our knowledge, we described the first application of in vivo FCI in breast cancer, demonstrating relevant biomarkers that could complement diagnosis of current imaging modalities, non-invasively and without contrast agents. Plain Language Summary Field cycling imaging (FCI) is a new medical imaging technique that uses low and variable magnetic fields to provide information on tissue properties that cannot be obtained by other medical imaging technologies. This study aimed at finding new types of signals from FCI images to better detect and characterise breast cancer. We acquired FCI images from people living with breast cancer at four different field strengths to demonstrate that low magnetic fields enable the detection of breast cancers without the need for potentially hazardous contrast agents unlike MRI systems. Additionally, we showed that the FCI technology has the potential to provide insights into tumour invasiveness, which is not visible with current imaging modalities. These findings suggest that FCI could complement existing clinical imaging techniques to improve the diagnosis of breast cancer. Mallikourti et al. assess whether breast cancer can be detected at low magnetic fields ranging from 2.3 mT to 200 mT using endogenous T 1 contrast, thereby eliminating the need for contrast agents. They show this method of field cycling imaging can differentiate invasive from non-invasive breast tumours in people with breast cancer.

Erythropoietin (Epo) is gaining interest in various neurological insults as a possible neuroprotective agent. We determined the effects of recombinant human Epo (rhEpo, 5000 IU per kg bw) on brain edema induced in rats by traumatic brain injury (TBI; impact-acceleration model; rhEpo administration 30 mins after injury). Magnetic resonance imaging (MRI) and a gravimetric technique were applied. In the MRI experiments, the apparent diffusion coefficient (ADC) and the tissue T1 relaxation time were measured hourly in the neocortex and caudoputamen, during a 6 h time span after TBI. In the gravimetric experiments, brain water content (BWC) was determined in these two regions, 6 h after TBI. Apparent diffusion coefficient measurements showed that rhEpo decreased brain edema early and durably. Gravimetric measurements showed that rhEpo decreased BWC at H6 in the neocortex as well as in the caudoputamen. No significant differences in ADC, in T1, or in BWC were found between rhEpo treated-TBI rats and sham-operated rats. Our findings show that post-traumatic administration of rhEpo can significantly reduce the development of brain edema in a model of diffuse TBI. Further studies should be conducted to identify the biochemical mechanisms involved in these immediate effects and to assess the use of rhEpo as a possible therapy for post-traumatic brain edema.

This paper describes a new rapid steady-state T1 (RSST1) method for mapping the cerebral blood volume fraction (CBVf) by magnetic resonance imaging (MRI). The principle is based on a two-compartment model of the brain (intra- and extravascular), and the effects of paramagnetic contrast agents on the intravascular longitudinal relaxation time T1. Using appropriate parameters, an Inversion-Recovery-Fast-Low-Angle-Shot sequence acts like a low pass T1 filter, suppressing signals from tissues with T1≫TR (TR=repetition time). It was shown in vivo that, exceeding a particular contrast agent dose, the signal reaches its maximum (corresponding to the intravascular equilibrium magnetization), and is maintained for a duration related to the dose. Acquisitions during this steady state divided by an additional measure of the overall (intra- and extravascular) magnetization at thermal equilibrium provides the CBVf. Experiments were performed on healthy rats at 2.35 T using P760 (Gd3+—compound from Guerbet Laboratories) and Gd-DOTA. Because of its high longitudinal relaxivity, P760 is more convenient, and was used to show the feasibility of the method. The CBVf in different structures of the rat brain was compared. The average CBVf for the whole brain slice is 3.29%±0.69% (n=15). The influence of transendothelial water exchange was quantified and transversal relaxation effects were found negligible in microvasculature. Finally, the sensitivity of the method to CBVf increases under hypercapnia was evaluated (1%/mm Hg PaCO2), demonstrating its potential for longitudinal studies and functional MRI. Clinical applications are feasible since equivalent results were obtained with Gd-DOTA.

In the central nervous system, microtubule-associated protein 6 (MAP6) is expressed at high levels and is crucial for cognitive abilities. The large spectrum of social and cognitive impairments observed in MAP6-KO mice are reminiscent of the symptoms observed in psychiatric diseases, such as schizophrenia, and respond positively to long-term treatment with antipsychotics. MAP6-KO mice have therefore been proposed to be a useful animal model for these diseases. Here, we explored the brain anatomy in MAP6-KO mice using high spatial resolution 3D MRI, including a volumetric T 1w method to image brain structures, and Diffusion Tensor Imaging (DTI) for white matter fiber tractography. 3D DTI imaging of neuronal tracts was validated by comparing results to optical images of cleared brains. Changes to brain architecture included reduced volume of the cerebellum and the thalamus and altered size, integrity and spatial orientation of some neuronal tracks such as the anterior commissure, the mammillary tract, the corpus callosum, the corticospinal tract, the fasciculus retroflexus and the fornix. Our results provide information on the neuroanatomical defects behind the neurological phenotype displayed in the MAP6-KO mice model and especially highlight a severe damage of the corticospinal tract with defasciculation at the location of the pontine nuclei.

This work shows that the longitudinal relaxation differences observed at very low magnetic fields between invasion/migration and proliferation processes on glioma mouse models in vivo are related to differences in the transmembrane water exchange basically linked to the aquaporin expression changes. Three glioma mouse models were used: Glio6 and Glio96 as invasion/migration models and U87 as cell proliferation model. In vivo proton longitudinal relaxation-rate constants (R1) at very low fields were measured by fast field cycling NMR (FFC-NMR). The tumor contribution to the observed proton relaxation rate, R1tum (U87: 12.26 ± 0.64 s−1; Glio6: 3.76 ± 0.88 s−1; Glio96: 6.90 ± 0.64 s−1 at 0.01 MHz), and the intracellular water lifetime, τin (U87: 826 ± 19 ms; Glio6: 516 ± 8 ms; Glio96: 596 ± 15 ms), were found to be good diagnostic hallmarks to distinguish invasion/migration from proliferation (p < 0.01 and 0.001). Overexpression of AQP4 and AQP1 were assessed in invasion/migration models, highlighting the pathophysiological role of these two aquaporins in water exchange that, in turn, determine the lower values in the observed R1 relaxation rate constant in glioma invasion/migration. Overall, our findings demonstrate that τin and R1 (measured at very low fields) are relevant biomarkers, discriminating invasion/migration from proliferation in vivo. These results highlight the use of FFC-NMR and FFC-imaging to assess the efficiency of drugs that could modulate aquaporin functions.

Structural microtubule associated proteins (MAPs) stabilize microtubules, a property that was thought to be essential for development, maintenance and function of neuronal circuits. However, deletion of the structural MAPs in mice does not lead to major neurodevelopment defects. Here we demonstrate a role for MAP6 in brain wiring that is independent of microtubule binding. We find that MAP6 deletion disrupts brain connectivity and is associated with a lack of post-commissural fornix fibres. MAP6 contributes to fornix development by regulating axonal elongation induced by Semaphorin 3E. We show that MAP6 acts downstream of receptor activation through a mechanism that requires a proline-rich domain distinct from its microtubule-stabilizing domains. We also show that MAP6 directly binds to SH3 domain proteins known to be involved in neurite extension and semaphorin function. We conclude that MAP6 is critical to interface guidance molecules with intracellular signalling effectors during the development of cerebral axon tracts. Loss of the structural microtubule-associated protein 6 (MAP6) leads to neuronal differentiation defects that are independent of MAP6’s microtubule-binding properties. Here the authors establish a functional link between MAP6 and Semaphorin 3E signalling for proper formation of the fornix of the brain.

To assess angiogenesis noninvasively in a C6 rat brain tumor model, the rapid-steady-state-T(1) (RSST(1)) magnetic resonance imaging (MRI) method was used for microvascular blood volume fraction (BVf) quantification with a novel contrast agent gadolinium per (3,6 anhydro) α-cyclodextrin (Gd-ACX). In brain tissue contralateral to the tumor, equal BVfs were obtained with Gd-ACX and the clinically approved gadoterate meglumine (Gd-DOTA). Contrary to Gd-DOTA, which leaks out of the tumor vasculature, Gd-ACX was shown to remain vascular in the tumor tissue allowing quantification of the tumor BVf. We sought to confirm the obtained tumor BVf using an independent method: instead of using a 'standard' two-dimensional histologic method, we study here how vascular morphometry combined with a stereological technique can be used for three-dimensional assessment of the vascular volume fraction (V(V)). The V(V) is calculated from the vascular diameter and length density. First, the technique is evaluated on simulated data and the healthy rat brain vasculature and is then applied to the same C6 tumor vasculature previously quantified by RSST(1)-MRI with Gd-ACX. The mean perfused V(V) and the BVf obtained by MRI in tumor regions are practically equal and the technique confirms the spatial heterogeneity revealed by MRI.

This paper describes a new rapid steady-state T 1 (RSS T 1 ) method for mapping the cerebral blood volume fraction ( CBVf) by magnetic resonance imaging (MRI). The principle is based on a two-compartment model of the brain (intra- and extravascular), and the effects of paramagnetic contrast agents on the intravascular longitudinal relaxation time T 1 . Using appropriate parameters, an Inversion-Recovery-Fast-Low-Angle-Shot sequence acts like a low pass T 1 filter, suppressing signals from tissues with T 1 ≫ TR ( TR=repetition time). It was shown in vivo that, exceeding a particular contrast agent dose, the signal reaches its maximum (corresponding to the intravascular equilibrium magnetization), and is maintained for a duration related to the dose. Acquisitions during this steady state divided by an additional measure of the overall (intra- and extravascular) magnetization at thermal equilibrium provides the CBVf. Experiments were performed on healthy rats at 2.35 T using P760 (Gd 3+ —compound from Guerbet Laboratories) and Gd-DOTA. Because of its high longitudinal relaxivity, P760 is more convenient, and was used to show the feasibility of the method. The CBVf in different structures of the rat brain was compared. The average CBVf for the whole brain slice is 3.29%±0.69% ( n=15). The influence of transendothelial water exchange was quantified and transversal relaxation effects were found negligible in microvasculature. Finally, the sensitivity of the method to CBVf increases under hypercapnia was evaluated (1%/mm Hg PaCO 2 ), demonstrating its potential for longitudinal studies and functional MRI. Clinical applications are feasible since equivalent results were obtained with Gd-DOTA.

To assess angiogenesis noninvasively in a C6 rat brain tumor model, the rapid-steady-state-T1 (RSST1) magnetic resonance imaging (MRI) method was used for microvascular blood volume fraction (BVf) quantification with a novel contrast agent gadolinium per (3,6 anhydro) α-cyclodextrin (Gd-ACX). In brain tissue contralateral to the tumor, equal BVfs were obtained with Gd-ACX and the clinically approved gadoterate meglumine (Gd-DOTA). Contrary to Gd-DOTA, which leaks out of the tumor vasculature, Gd-ACX was shown to remain vascular in the tumor tissue allowing quantification of the tumor BVf. We sought to confirm the obtained tumor BVf using an independent method: instead of using a ‘standard’ two-dimensional histologic method, we study here how vascular morphometry combined with a stereological technique can be used for three-dimensional assessment of the vascular volume fraction (VV). The VV is calculated from the vascular diameter and length density. First, the technique is evaluated on simulated data and the healthy rat brain vasculature and is then applied to the same C6 tumor vasculature previously quantified by RSST1-MRI with Gd-ACX. The mean perfused VV and the BVf obtained by MRI in tumor regions are practically equal and the technique confirms the spatial heterogeneity revealed by MRI.