35 research outputs found
Manganese-Enhanced Tâ Mapping in the Myocardium of Normal and Infarcted Hearts
Background. Manganese-enhanced MRI (MEMRI) has the potential to identify viable myocardium and quantify calcium influx and handling. Two distinct manganese contrast media have been developed for clinical application, mangafodipir and EVP1001-1, employing different strategies to mitigate against adverse effects resulting from calcium-channel agonism. Mangafodipir delivers manganese ions as a chelate, and EVP1001-1 coadministers calcium gluconate. Using myocardial T1 mapping, we aimed to explore chelated and nonchelated manganese contrast agents, their mechanism of myocardial uptake, and their application to infarcted hearts. Methods. T1 mapping was performed in healthy adult male Sprague-Dawley rats using a 7T MRI scanner before and after nonchelated (EVP1001-1 or MnCl2 (22âÎŒmol/kg)) or chelated (mangafodipir (22â44âÎŒmol/kg)) manganese-based contrast media in the presence of calcium channel blockade (diltiazem (100â200âÎŒmol/kg/min)) or sodium chloride (0.9%). A second cohort of rats underwent surgery to induce anterior myocardial infarction by permanent coronary artery ligation or sham surgery. Infarcted rats were imaged with standard gadolinium delayed enhancement MRI (DEMRI) with inversion recovery techniques (DEMRI inversion recovery) as well as DEMRI T1 mapping. A subsequent MEMRI scan was performed 48âh later using either nonchelated or chelated manganese and T1 mapping. Finally, animals were culled at 12 weeks, and infarct size was quantified histologically with Massonâs trichrome (MTC). Results. Both manganese agents induced concentration-dependent shortening of myocardial T1 values. This was greatest with nonchelated manganese, and could be inhibited by 30â43% with calcium-channel blockade. Manganese imaging successfully delineated the area of myocardial infarction. Indeed, irrespective of the manganese agent, there was good agreement between infarct size on MEMRI T1 mapping and histology (bias 1.4%, 95% CI â14.8 to 17.1 P>0.05). In contrast, DEMRI inversion recovery overestimated infarct size (bias 11.4%, 95% CI â9.1 to 31.8 P=0.002), as did DEMRI T1 mapping (bias 8.2%, 95% CI â10.7 to 27.2 P=0.008). Increased manganese uptake was also observed in the remote myocardium, with remote myocardial âT1 inversely correlating with left ventricular ejection fraction after myocardial infarction (r=â0.61, P=0.022). Conclusions. MEMRI causes concentration and calcium channel-dependent myocardial T1 shortening. MEMRI with T1 mapping provides an accurate assessment of infarct size and can also identify changes in calcium handling in the remote myocardium. This technique has potential applications for the assessment of myocardial viability, remodelling, and regeneration.</jats:p
Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment
ACKNOWLEDGMENTS Schematic diagrams in Figures 2, 8 are created withBiorender.com. FUNDING We gratefully acknowledge the grant support from the Alzheimerâs Society (152 (PG-157); 290 (AS-PG-15b-018); 228 (AS-DTC-2014-017), 314 (AS âPhD-16-006), and Alzheimerâs Research United Kingdom (ART-PG2010-3; ARUK-PG2013- 22; ARUK-PG2016B-6), and The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). ML and JB are funded by an Alzheimerâs Society Scotland Doctoral Training Programme and RS Macdonald Trust. ML was also funded by a China Scholarship Council (CSC)/University of Edinburgh scholarship.Peer reviewedPublisher PD
Imaging learned fear circuitry in awake mice using fMRI
Functional magnetic resonance imaging (fMRI) of learned behaviour in âawake rodentsâ provides the opportunity for translational preclinical studies into the influence of pharmacological and genetic manipulations on brain function. fMRI has recently been employed to investigate learned behaviour in awake rats. Here, this methodology is translated to mice, so that future fMRI studies may exploit the vast number of genetically modified mouse lines that are available. One group of mice was conditioned to associate a flashing light (conditioned stimulus, CS) with foot shock (PG; paired group), and another group of mice received foot shock and flashing light explicitly unpaired (UG; unpaired group). The blood oxygen level-dependent signal (proxy for neuronal activation) in response to the CS was measured 24 h later in awake mice from the PG and UG using fMRI. The amygdala, implicated in fear processing, was activated to a greater degree in the PG than in the UG in response to the CS. Additionally, the nucleus accumbens was activated in the UG in response to the CS. Because the CS signalled an absence of foot shock in the UG, it is possible that this region is involved in processing the safety aspect of the CS. To conclude, the first use of fMRI to visualise brain activation in awake mice that are completing a learned emotional task is reported. This work paves the way for future preclinical fMRI studies to investigate genetic and environmental influences on brain function in transgenic mouse models of disease and aging
The role of Brain Derived Neurotrophic Factor in learned fear processing: an awake rat fMRI study
Brain-derived neurotrophic factor (BDNF) signaling is implicated in the aetiology of many psychiatric disorders associated with altered emotional processing. Altered peripheral (plasma) BDNF levels have been proposed as a biomarker for neuropsychiatric disease risk in humans. However the relationship between peripheral and central BDNF levels and emotional brain activation is unknown. We used heterozygous BDNF knockdown rats (BDNF+/- ) to examine the effects of genetic variation in the BDNF gene on peripheral and central BDNF levels and emotional brain activation as assessed by awake fMRI. BDNF+/- and control rats were trained to associate a flashing light (conditioned stimulus; CS) with foot-shock, and brain activation in response to the CS was measured 24h later in awake rats using fMRI. Central and peripheral BDNF levels were decreased in BDNF+/- rats compared to control rats. Activation of fear circuitry (amygdala, periaqueductal gray, granular insular) was seen in control animals, however activation of this circuitry was absent in BDNF+/- animals. Behavioral experiments confirmed impaired conditioned fear responses in BDNF+/- rats, despite intact innate fear responses. These data confirm a positive correlation (r = 0.86, 95% CI [0.55, 0.96]; P = 0.0004) between peripheral and central BDNF levels and indicate a functional relationship between BDNF levels and emotional brain activation as assessed by fMRI. The results demonstrate the use of rodent fMRI as a sensitive tool for measuring brain function in preclinical translational studies using genetically modified rats and support the use of peripheral BDNF as a biomarker of central affective processing
Functionalized superparamagnetic iron oxide nanoparticles provide highly efficient iron-labelling in macrophages for magnetic resonance-based detection in vivo
Tracking cells during regenerative cytotherapy is crucial for monitoring their safety and efficacy. Macrophages are an emerging cell-based regenerative therapy for liver disease and can be readily labeled for medical imaging. A reliable, clinically applicable cell-tracking agent would be a powerful tool to study cell biodistribution.Using a recently described chemical design, we set out to functionalize, optimize and characterize a new set of superparamagnetic iron oxide nanoparticles (SPIONs) to efficiently label macrophages for magnetic resonance imaging-based cell tracking in vivo.A series of cell health and iron uptake assays determined that positively charged SPIONs (+16.8âmV) could safely label macrophages more efficiently than the formerly approved ferumoxide (-6.7âmV; Endorem) and at least 10 times more efficiently than the clinically approved SPION ferumoxytol (-24.2âmV; Rienso). An optimal labeling time of 4âh at 25â”g/mL was demonstrated to label macrophages of mouse and human origin without any adverse effects on cell viability whilst providing substantial iron uptake (>5âpg Fe/cell) that was retained for 7 days in vitro. SPION labeling caused no significant reduction in phagocytic activity and a shift toward a reversible M1-like phenotype in bone marrow-derived macrophages (BMDMs). Finally, we show that SPION-labeled BMDMs delivered via the hepatic portal vein to mice are localized in the hepatic parenchyma resulting in a 50% drop in T2* in the liver. Engraftment of exogenous cells was confirmed via immunohistochemistry up to 3 weeks posttransplantation.A positively charged dextran-coated SPION is a promising tool to noninvasively track hepatic macrophage localization for therapeutic monitoring
Multicentre evaluation of MRI variability in the quantification of infarct size in experimental focal cerebral ischaemia
Ischaemic stroke is a leading cause of death and disability in the developed world.
Despite that considerable advances in experimental research enabled understanding
of the pathophysiology of the disease and identified hundreds of potential
neuroprotective drugs for treatment, no such drug has shown efficacy in humans. The
failure in the translation from bench to bedside has been partially attributed to the
poor quality and rigour of animal studies. Recently, it has been suggested that
multicentre animal studies imitating the design of randomised clinical trials could
improve the translation of experimental research. Magnetic resonance imaging (MRI)
could be pivotal in such studies due to its non-invasive nature and its high sensitivity
to ischaemic lesions, but its accuracy and concordance across centres has not yet been
evaluated.
This thesis focussed on the use of MRI for the assessment of late infarct size, the
primary outcome used in stroke models. Initially, a systematic review revealed that a
plethora of imaging protocols and data analysis methods are used for this purpose.
Using meta-analysis techniques, it was determined that T2-weighted imaging (T2WI)
was best correlated with gold standard histology for the measurement of infarctbased
treatment effects. Then, geometric accuracy in six different preclinical MRI
scanners was assessed using structural phantoms and automated data analysis tools
developed in-house. It was found that geometric accuracy varies between scanners,
particularly when centre-specific T2WI protocols are used instead of a standardised
protocol, though longitudinal stability over six months is high. Finally, a simulation
study suggested that the measured geometric errors and the different protocols are
sufficient to render infarct volumes and related group comparisons across centres
incomparable. The variability increases when both factors are taken into account and
when infarct volume is expressed as a relative estimate. Data in this study were
analysed using a custom-made semi-automated tool that was faster and more reliable
in repeated analyses than manual analysis.
Findings of this thesis support the implementation of standardised methods for the
assessment and optimisation of geometric accuracy in MRI scanners, as well as image
acquisition and analysis of in vivo data for the measurement of infarct size in
multicentre animal studies. Tools and techniques developed as part of the thesis show
great promise in the analysis of phantom and in vivo data and could be a step towards
this endeavour