Size-tuneable nanometric MRI contrast agents for the imaging of molecular weight dependent transport processes

Purpose: To evaluate size-tuneable nanomeric glycol-chitosan-DTPA-Gd conjugates as MRI contrast agents for the imaging of molecular weight (MW) dependent transport processes. Material & Methods: Glycol chitosans (GC) – DTPA conjugates of precisely controlled MWs were synthesised and evaluated in mice against Gd-DTPA using times series of high-resolution MRI images of trunk, head, and xenograft flank tumours. All animal studies were approved by the local ethics committee and the UK authorities. Results: GC-DTPA modification ratio was one DTPA per 3.9 – 5.13 of GC monomers. GC-DTAPGd provided overall superior contrast compared to Gd-DTPA with the duration of the enhancement depending on MW (≥ 1h for 40kD). Kidneys showed early enhancement also in the renal pelvis suggesting renal elimination. Imaging of the head with GC-DTPA-Gd allowed detailed anatomical identification of specific blood vessels in particular with the high MW agent. Sequential high-resolution isotropic imaging of established A431 xenograft flank tumours with DTPA-Gd and GC-DTPA-Gd demonstrated that the initial delivery of the contrast agents was well correlated with blood supply. Subsequent tissue transport was primarily by diffusion and was limited by molecular weight. The data also highlight the role of heterogeneity in CA distribution that was again more prominent for the high MW agent. Conclusion: GC-DTPA-Gd with identical physical chemical properties but precisely controlled MW allow isotropic high-resolution three-dimensional imaging of molecular weight dependent transport processes which could potentially lead to clinical biomarkers for molecular weight dependent drug transport and support selection of suitable tumour models for pre-clinical development

Stroke penumbra defined by an MRI-based oxygen challenge technique: 2. Validation based on the consequences of reperfusion

Magnetic resonance imaging (MRI) with oxygen challenge (T2* OC) uses oxygen as a metabolic biotracer to define penumbral tissue based on CMRO2 and oxygen extraction fraction. Penumbra displays a greater T2* signal change during OC than surrounding tissue. Since timely restoration of cerebral blood flow (CBF) should salvage penumbra, T2* OC was tested by examining the consequences of reperfusion on T2* OC-defined penumbra. Transient ischemia (109±20 minutes) was induced in male Sprague-Dawley rats (n=8). Penumbra was identified on T2*-weighted MRI during OC. Ischemia and ischemic injury were identified on CBF and apparent diffusion coefficient maps, respectively. Reperfusion was induced and scans repeated. T2 for final infarct and T2* OC were run on day 7. T2* signal increase to OC was 3.4% in contralateral cortex and caudate nucleus and was unaffected by reperfusion. In OC-defined penumbra, T2* signal increased by 8.4%±4.1% during ischemia and returned to 3.25%±0.8% following reperfusion. Ischemic core T2* signal increase was 0.39%±0.47% during ischemia and 0.84%±1.8% on reperfusion. Penumbral CBF increased from 41.94±13 to 116.5±25 mL per 100 g per minute on reperfusion. On day 7, OC-defined penumbra gave a normal OC response and was located outside the infarct. T2* OC-defined penumbra recovered when CBF was restored, providing further validation of the utility of T2* OC for acute stroke management

Stroke penumbra defined by an MRI-based oxygen challenge technique: 1. validation using [14C]2-deoxyglucose autoradiography

Accurate identification of ischemic penumbra will improve stroke patient selection for reperfusion therapies and clinical trials. Current magnetic resonance imaging (MRI) techniques have limitations and lack validation. Oxygen challenge T2* MRI (T2* OC) uses oxygen as a biotracer to detect tissue metabolism, with penumbra displaying the greatest T2* signal change during OC. [14C]2-deoxyglucose (2-DG) autoradiography was combined with T2* OC to determine metabolic status of T2*-defined penumbra. Permanent middle cerebral artery occlusion was induced in anesthetized male Sprague-Dawley rats (n=6). Ischemic injury and perfusion deficit were determined by diffusion- and perfusion-weighted imaging, respectively. At 147±32 minutes after stroke, T2* signal change was measured during a 5-minute 100% OC, immediately followed by 125 μCi/kg 2-DG, intravenously. Magnetic resonance images were coregistered with the corresponding autoradiograms. Regions of interest were located within ischemic core, T2*-defined penumbra, equivalent contralateral structures, and a region of hyperglycolysis. A T2* signal increase of 9.22%±3.9% (mean±s.d.) was recorded in presumed penumbra, which displayed local cerebral glucose utilization values equivalent to contralateral cortex. T2* signal change was negligible in ischemic core, 3.2%±0.78% in contralateral regions, and 1.41%±0.62% in hyperglycolytic tissue, located outside OC-defined penumbra and within the diffusion abnormality. The results support the utility of OC-MRI to detect viable penumbral tissue follow

Potential use of oxygen as a metabolic biosensor in combination with T2*-weighted MRI to define the ischemic penumbra

We describe a novel magnetic resonance imaging technique for detecting metabolism indirectly through changes in oxyhemoglobin:deoxyhemoglobin ratios and T2* signal change during ‘oxygen challenge’ (OC, 5 mins 100% O2). During OC, T2* increase reflects O2 binding to deoxyhemoglobin, which is formed when metabolizing tissues take up oxygen. Here OC has been applied to identify tissue metabolism within the ischemic brain. Permanent middle cerebral artery occlusion was induced in rats. In series 1 scanning (n=5), diffusion-weighted imaging (DWI) was performed, followed by echo-planar T2* acquired during OC and perfusion-weighted imaging (PWI, arterial spin labeling). Oxygen challenge induced a T2* signal increase of 1.8%, 3.7%, and 0.24% in the contralateral cortex, ipsilateral cortex within the PWI/DWI mismatch zone, and ischemic core, respectively. T2* and apparent diffusion coefficient (ADC) map coregistration revealed that the T2* signal increase extended into the ADC lesion (3.4%). In series 2 (n=5), FLASH T2* and ADC maps coregistered with histology revealed a T2* signal increase of 4.9% in the histologically defined border zone (55% normal neuronal morphology, located within the ADC lesion boundary) compared with a 0.7% increase in the cortical ischemic core (92% neuronal ischemic cell change, core ADC lesion). Oxygen challenge has potential clinical utility and, by distinguishing metabolically active and inactive tissues within hypoperfused regions, could provide a more precise assessment of penumbra

Assessment of the impact of the scanner-related factors on brain morphometry analysis with Brainvisa.

BACKGROUND: Brain morphometry is extensively used in cross-sectional studies. However, the difference in the estimated values of the morphometric measures between patients and healthy subjects may be small and hence overshadowed by the scanner-related variability, especially with multicentre and longitudinal studies. It is important therefore to investigate the variability and reliability of morphometric measurements between different scanners and different sessions of the same scanner. METHODS: We assessed the variability and reliability for the grey matter, white matter, cerebrospinal fluid and cerebral hemisphere volumes as well as the global sulcal index, sulcal surface and mean geodesic depth using Brainvisa. We used datasets obtained across multiple MR scanners at 1.5 T and 3 T from the same groups of 13 and 11 healthy volunteers, respectively. For each morphometric measure, we conducted ANOVA analysis and verified whether the estimated values were significantly different across different scanners or different sessions of the same scanner. The between-centre and between-visit reliabilities were estimated from their contribution to the total variance, using a random-effects ANOVA model. To estimate the main processes responsible for low reliability, the results of brain segmentation were compared to those obtained using FAST within FSL. RESULTS: In a considerable number of cases, the main effects of both centre and visit factors were found to be significant. Moreover, both between-centre and between-visit reliabilities ranged from poor to excellent for most morphometric measures. A comparison between segmentation using Brainvisa and FAST revealed that FAST improved the reliabilities for most cases, suggesting that morphometry could benefit from improving the bias correction. However, the results were still significantly different across different scanners or different visits. CONCLUSIONS: Our results confirm that for morphometry analysis with the current version of Brainvisa using data from multicentre or longitudinal studies, the scanner-related variability must be taken into account and where possible should be corrected for. We also suggest providing some flexibility to Brainvisa for a step-by-step analysis of the robustness of this package in terms of reproducibility of the results by allowing the bias corrected images to be imported from other packages and bias correction step be skipped, for example.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Magnetic Resonance Imaging to Assess Blood–Brain Barrier Damage in Murine Trypanosomiasis

The ability of trypanosomes to invade the brain and induce an inflammatory reaction is well-recognized. This study uses magnetic resonance imaging (MRI) in conjunction with a murine model of central nervous system (CNS) stage trypanosomiasis to investigate this phenomenon at the level of the blood–brain barrier (BBB). Mice were scanned before and after administration of the contrast agent. Signal enhancement maps were generated, and the percentage signal change was calculated. The severity of the neuroinflammation was also assessed. Statistical analysis of the signal change data revealed a significantly (P = 0.028) higher signal enhancement in mice at 28 days post-infection (least squares mean = 26.709) compared with uninfected animals (6.298), indicating the presence of BBB impairment. Leukocytes were found in the meninges and perivascular space of some blood vessels in the infected mice. This study shows that the integrity of the BBB is compromised during CNS stage trypanosomiasis and that the impairment does not correlate with inflammatory cell infiltration

A physical and clinical evaluation of a fixed angle nuclear tomographic cardiac imaging system

The conventional planar imaging techniques of nuclear medicine may be limited in terms of diagnostic accuracy by contributions to the image from isotope uptake in non-target organs which under or overlie the organ of interest. Similarly contributions from healthy sections of the target organ may mask under or overlying abnormal sections. Various tomographic techniques have been introduced to overcome this problem by producing images of a number of reconstructed planes at different depths through the target organ. This thesis is an evaluation in both physical and clinical terms of one such device (the 7 pinhole collimator) which is used primarily in the imaging of the left ventricular myocardium and blood pool. The 7 pinhole and another fixed angle tomographic system (the Rotating Slant Hole) are compared and evaluated in terms of planar and depth resolutions, reconstructed and acquired sensitivities, uniformities, reconstruction volumes and the effects of scatter. The Rotating Slant Hole is found to have a better physical performance but its low sensitivity and inappropriate reconstruction volume are considered to impose certain limits an its applicability to the clinical situation. An attempt is made to improve the resolution of the 7 pinhole by applying a non-linearity correction to the raw data. The theoretical and experimental accuracy of this technique is established and is found to significantly improve the system resolution with depth. Software generated distortions are introduced into the raw data in order todetermine the effect of various degrees of non-linearity on the resolution. A technique is developed to quantify uptake segmentally in thallium-201 perfusion images. This technique is used to determine theeffects of malrotated and off-centre acquisitions on the production of artefactual defects during tanographic reconstruction. Studies with a left ventricular myocardium phantom reveal that the 7 pinhole is able to detect smaller lesions than the conventional planar technique but both the non-linearity correction and the impedance operator are found in practice not to improve on this. In a group of 26 patients no significant difference was found however in the diagnostic accuracy of the 7 pinhole and planar techniques in the diagnosis of myocardial infarction.The 7 pinhole system is used for blood pool analysis in a dynamic phantom model and in patients . A study of 20 patients revealed the technique to be as accurate as the planar technique in the detection of wall motion abnormalities and more accurate in the identification of dyskinetic segments provided phase analysis was used in conjunction with the reconstructed blood pool images. The model studies reveal the limits of the systems tanographic ability in the case of aneurysmal ventricles.</p