This paper describes a new rapid steady-state T 1 (RSST 1 ) method for mapping the cerebral blood volume fraction (CBVf) by magnetic resonance imaging (MRI). The principle is based on a twocompartment 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 bTR (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%60.69% (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.
Schistosomiasis, a neglected tropical disease, is a major cause of chronic morbidity and disability, and premature death. The hepatosplenic form of schistosomiasis is characterized by hepatosplenomegaly, liver fibrosis, portal hypertension and oesophageal varices, whose rupture may cause bleeding and death. We review currently available abdominal imaging modalities and describe their basic principles, strengths, weaknesses, and usefulness in the assessment of hepatosplenic schistosomiasis. Advanced imaging methods are presented that could be of interest for hepatosplenic schistosomiasis evaluation by yielding morphological, functional and molecular parameters of disease progression. We also provide a comprehensive view of preclinical imaging studies and current research objectives such as parasite visualisation in hosts, follow-up of host-immune response, and development of non-invasive quantitative methods for liver fibrosis assessment.
Monitoring glioma cell infiltration in the brain is critical for diagnosis and therapy. Using a new glioma Glio6 mouse model derived from human stem cells we show how diffusion tensor imaging (DTI) may predict glioma cell migration/invasion. In vivo multiparametric MRI was performed at one, two and three months of Glio6 glioma growth (Glio6 (n = 6), sham (n = 3)). This longitudinal study reveals the existence of a time window to study glioma cell/migration/invasion selectively. Indeed, at two months only Glio6 cell invasion was detected, while tumor mass formation, edema, blood-brain barrier leakage and tumor angiogenesis were detected later, at three months. To robustly confirm the potential of DTI for detecting glioma cell migration/invasion, a microscopic 3D-DTI (80 μm isotropic spatial resolution) technique was developed and applied to fixed mouse brains (Glio6 (n = 6), sham (n = 3)). DTI changes were predominant in the corpus callosum (CC), a known path of cell migration. Fractional anisotropy (FA) and perpendicular diffusivity (D ) changes derived from ex vivo microscopic 3D-DTI were significant at two months of tumor growth. In the caudate putamen an FA increase of +38% (p < 0.001) was observed, while in the CC a - 28% decrease in FA (p < 0.005) and a + 95% increase in D (p < 0.005) were observed. In the CC, DTI changes and fluorescent Glio6 cell density obtained by two-photon microscopy in the same brains were correlated (p < 0.001, r = 0.69), validating FA and D as early quantitative biomarkers to detect glioma cell migration/invasion. The origin of DTI changes was assessed by electron microscopy of the same tract, showing axon bundle disorganization. During the first two months, Glio6 cells display a migratory phenotype without being associated with the constitution of a brain tumor mass. This offers a unique opportunity to apply microscopic 3D-DTI and to validate DTI parameters FA and D as biomarkers for glioma cell invasion.
In magnetic resonance imaging (MRI), cerebral blood volume (CBV) quantification is dependent on the MRI sequence and on the properties of the contrast agents (CAs). By using the rapid steadystate T 1 method, we show the potential of gadolinium per (3,6-anhydro) a-cyclodextrin (Gd-ACX), a new MRI paramagnetic CA (inclusion complex of Gd 3 + with per (3,6-anhydro)-a-cyclodextrin), for the CBV quantification in the presence of blood-brain barrier lesions. After biocompatibility and relaxivity experiments, in vivo experiments on rats were performed on a C6 tumor model with 0.05 mmol Gd-ACX/kg ( < 1/10 of the median lethal dose) injected at a 25 mmol/L concentration, inducing neither nephrotoxicity nor hemolysis. On T 1 -weighted images, a signal enhancement of 170% appeared in vessels after injection, but not in the tumor (during the 1 h of observation), in contrast to the 90% signal enhancement obtained with Gd-DOTA (a clinical MRI CA) injected at a T 1 isoefficient dose. This result shows the absence of Gd-ACX extravasation into the tumor tissue and its confinement to the vascular space. Fractional CBV values were found similar to Gd-ACX and Gd-DOTA in healthy brain tissue and in the contralateral hemisphere of tumor-bearing rats, whereas only Gd-ACX was appropriate for CBV quantification in tumor regions.
The use of pharmacologic MRI (phMRI) in mouse models of brain disorders allows noninvasive in vivo assessment of drug-modulated local cerebral blood volume changes (ΔCBV) as one correlate of neuronal and neuro-vascular activities. In this report, we employed CBV weighted phMRI to compare cocaine-modulated neuronal activity in dopamine transporter (DAT) knockout (KO) and wild-type mice. Cocaine acts to block the dopamine, norepinephrine and serotonin transporters (DAT, NET and SERT) that clear their respective neurotransmitters from the synapses, helping to terminate cognate neurotransmission. Cocaine consistently reduced CBV, with a similar pattern of regional ΔCBV in brain structures involved in mediating reward in both DAT genotypes. The largest effects (−20% to −30% ΔCBV) were seen in the nucleus accumbens and several cortical regions. Decreasing response amplitudes to cocaine were noted in more posterior components of the cortico-mesolimbic circuit. DAT KO mice had significantly attenuated ΔCBV amplitudes, shortened times to peak response and reduced response duration in most regions. This study demonstrates that DAT knockout does not abolish the phMRI responses to cocaine, suggesting that adaptations to loss of DAT and/or retained cocaine activity in other monoamine neurotransmitter systems underlie these responses in DAT KO mice.
This work demonstrates how the rapid steady state T1 MRI technique for cerebral blood volume fraction (BVf) quantification can be used with intraperitoneal Gd-DOTA injections in mice at 4.7 T. The peak signal amplitude after intravenous administration (0.7 mmol/kg) and the steady state signal amplitude reached 15 min after intraperitoneal administration (6 mmol/kg) in the same mice lead to equivalent BVf measures in the order of 0.02 in the brain. The resulting time window for BVf quantification is ≈30 min and allows for cerebral BVf mapping with increased spatial resolution or signal-to-noise ratio, or for monitoring functional BVf changes. A cerebral BVf increase of up to 25% induced by the vasodilator acetazolamide was observed, validating the vascular origin of the signal. The noninvasive and quantitative rapid steady state T1 technique can be used in serial studies to evaluate new drugs or disease models, such as antiangiogenic therapies in tumors.
Straightforward tumor BVf quantification without AIF determination is demonstrated in presence of CA leakage. The method will facilitate angiogenesis assessment in longitudinal neuro-oncologic studies in particular when monitoring the response to antiangiogenic therapies.
Pharmacologic MRI (phMRI) uses functional MRI techniques to provide a non-invasive in vivo measurement of the hemodynamic effects of drugs. The cerebral blood volume change (ΔCBV) serves as a surrogate for neuronal activity via neurovascular coupling mechanisms. By assessing the location and time course of brain activity in mouse mutant studies, phMRI can provide valuable insights into how different behavioral phenotypes are expressed in differing brain activity response to drug challenge. In this report, we evaluate the utility of three different intravascular ultrasmall superparamagnetic iron oxide (USPIO) contrast agents for phMRI using a gradient-echo technique with temporal resolution of one minute at high magnetic field. The tissue half life of the USPIOs was studied using a nonlinear detrending model. All three studied USPIOs are candidates for CBV weighted phMRI-experiments, with r2/r1 ratios ≥ 20 and apparent half-lives ≥ 1.5 h at the described doses. An echo time of about 10 ms or longer results in a fCNR > 75 after USPIO injection, with negligible decrease during 1.5 to 2 hours. phMRI experiments were conducted at 7T using cocaine as a psychotropic substance and acetazolamide, a global vasodilator, as a positive control. Cocaine acts as a dopamine-serotonin-norepinephrine reuptake inhibitor, increasing extracellular concentrations of these neurotransmitters and thus increasing dopaminergic, serotonergic and noradrenergic neurotransmission. phMRI indicated that CBV was reduced in the normal mouse brain after cocaine challenge, with largest effects in nucleus accumbens, while after acetazolamide the blood volume was increased in both cerebral and extra-cerebral tissue.
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