Biomedical subjects

Klaas Nicolay

Publications and source records attributed to Klaas Nicolay.

At least 19 recordsLinked to original sources

PubMed2007

Early in vivo assessment of angiostatic therapy efficacy by molecular MRI.

Noninvasive diagnostic imaging methods to establish the efficacy of angiostatic therapies are becoming increasingly important with the first Food and Drug Administration approvals of such agents. Magnetic resonance molecular imaging is an imaging technique that allows the visualization of pathological processes in vivo with a better spatial resolution as compared with nuclear methods, such as photon emission tomography and single photon emission computed tomography. In this study, we used alpha(v)beta3 targeted bimodal liposomes to quantitate angiogenesis in a tumor mouse model with magnetic resonance imaging (MRI) and to evaluate the therapeutic efficacy of the angiogenesis inhibitors anginex and endostatin. The MRI findings were validated with fluorescence microscopy and showed a very good correlation with the microvessel density. In conclusion, this study provides evidence that molecular MRI can be used to noninvasively measure the efficacy of angiogenesis inhibitors during the course of therapy.

Angiogenesis Inhibitors↗

PubMed2007

Quantitative MRI-pathology correlations of brain white matter lesions developing in a non-human primate model of multiple sclerosis.

Experimental autoimmune encephalomyelitis (EAE) induced with recombinant human myelin/oligodendrocyte glycoprotein in the common marmoset is a useful preclinical model of multiple sclerosis in which white matter lesions can be well visualized with MRI. In this study we characterized lesion progression with quantitative in vivo MRI (4.7 T; T(1) relaxation time +/- Gd-DTPA; T(2) relaxation time; magnetization transfer ratio, MTR, imaging) and correlated end stage MRI presentation with quantitative ex vivo MRI (formaldehyde fixed brains; T(1) and T(2) relaxation times; MTR) and histology. The histopathological characterization included axonal density measurements and the numeric quantification of infiltrated macrophages expressing markers for early active [luxol fast blue (LFB) or migration inhibition factor-related protein-14 positive] or late active/inactive [periodic acid Schiff (PAS) positive] demyelinating lesion. MRI experiments were done every two weeks until the monkeys were sacrificed with severe EAE-related motor deficits. Compared with the normal appearing white matter, lesions showed an initial increase in T(1) relaxation times, leakage of Gd-DTPA and decrease in MTR values. The progressive enlargement of lesions was associated with stabilized T(1) values, while T(2) initially increased and stabilized thereafter and MTR remained decreased. Gd-DTPA leakage was highly variable throughout the experiment. MRI characteristics of the cortex and (normal appearing) white matter did not change during the experiment. We observed that in vivo MTR values correlated positively with the number of early active (LFB+) and negatively with late active (PAS+) macrophages. Ex vivo MTR and relaxation times correlated positively with the number of PAS-positive macrophages. None of the investigated MRI parameters correlated with axonal density.

Animals↗

PubMed2007

Comparison between prospective and retrospective triggering for mouse cardiac MRI.

High-resolution magnetic resonance imaging (MRI) has evolved into one of the major non-invasive tools to study the healthy and diseased mouse heart. This study presents a Cartesian CINE MRI protocol based on a fast low-angle shot sequence with a navigator echo to generate cardiac triggering and respiratory gating signals retrospectively, making the use of ECG leads and respiratory motion sensors obsolete. MRI of the in vivo mouse heart using this sequence resulted in CINE images with no detectable cardiac and respiratory motion artefacts. The retrospective method allows for steady-state imaging of the mouse heart, which is essential for quantitative contrast-enhanced MRI studies. A comparison was made between prospective and retrospective methods in terms of the signal-to-noise ratio and the contrast-to-noise ratio between blood and myocardial wall, as well as global cardiac functional indices: end-diastolic volume, end-systolic volume, stroke volume and ejection fraction. The retrospective method resulted in almost constant left-ventricle wall signal intensity throughout the cardiac cycle, at the expense of a decrease in the signal-to-noise ratio and the contrast-to-noise ratio between blood and myocardial wall as compared with the prospective method. Prospective and retrospective sequences yielded comparable global cardiac functional indices. The largest mean relative difference found was 8% for the end-systolic volume.

Algorithms↗

PubMed2006

Functional MRI reveals declined prefrontal cortex activation in patients with epilepsy on topiramate therapy.

Functional magnetic resonance imaging of covert word generation was used to examine brain activation abnormalities associated with topiramate-induced cognitive language impairment in patients with epilepsy. Compared with a control epilepsy group, in the topiramate-treated group, there was significantly less activation in the language-mediating regions of the prefrontal cortex; the topiramate group also had significantly lower neuropsychological language scores. These findings suggest that topiramate has a critical effect on the cerebral neural systems that mediate expressive language.

Adult↗

PubMed2006

Increased resistance to fatigue in creatine kinase deficient muscle is not due to improved contractile economy.

There has been speculation on the origin of the increased endurance of skeletal muscles in creatine kinase (CK)-deficient mice. Important factors that have been raised include the documented increased mitochondrial capacity and alterations in myosin heavy chain (MyHC) isoform composition in CK-deficient muscle. More recently, the absence of inorganic phosphate release from phosphocreatine hydrolysis in exercising CK-deficient muscle has been postulated to contribute to the lower fatigueability in skeletal muscle. In this study, we tested the hypothesis that the reported shift in MyHC composition to slower isoforms in CK-deficient muscle leads to a decrease in oxygen cost of twitch performance. To that aim, extensor digitorum longus (EDL) and soleus (SOL) muscles were isolated from wild-type (WT) and knock-out mice deficient in the cytoplasmic muscle-type and sarcomeric mitochondrial isoenzymes of CK, and oxygen consumption per twitch time-tension-integral (TTI) was measured. The results show that the adaptive response to loss of CK function does not involve any major change to contractile economy of skeletal muscle.

Animals↗

PubMed2006

Monitoring of moisture redistribution in multicomponent food systems by use of magnetic resonance imaging.

Differences in water activity within multicomponent food systems inevitably lead to moisture (re)distribution phenomena, hence deteriorating textural quality during shelf life. Noninvasive assessment of moisture transport in such systems would promote mechanistic understanding and enable rational development of strategies to control migration. Magnetic resonance imaging (MRI) is an ideal candidate for such a measurement technique, but its use in systems with low-moisture components (e.g., cereal materials) is seriously hampered because of reduced transverse relaxation times. In this work, we report two MRI protocols for the noninvasive and quantitative assessment of moisture transport in multicomponent food products. The first protocol is suitable to study relatively slow (days/weeks) processes, whereas the second one is designed to study fast (hours) moisture transport. We have successfully applied this methodology to quantify moisture transport within multicomponent food systems, with adequate temporal and spatial resolution.

Food Analysis↗

PubMed2006

Liposome-enhanced MRI of neointimal lesions in the ApoE-KO mouse.

Conventional high-resolution MRI is capable of detecting lipid-rich atherosclerotic plaques in both human atherosclerosis and animal models of atherosclerosis. In this study we induced neointimal lesions in ApoE-KO mice by placing a constrictive collar around the right carotid artery. The model was imaged with conventional multispectral MRI, and the thickened wall could not be distinguished from surrounding tissue. We then tested paramagnetic liposomes (mean size=90 nm) for their ability to improve MRI visualization of induced thickening, using Gd-DTPA as a control. T1-weighted (T1-w), black-blood MRI of the neck area of the mice was performed before and 15 min, 45 min, and 24 hr after intravenous injection of either paramagnetic liposomes or Gd-DTPA. The collared vessel wall of mice that were injected with liposomes showed a pronounced signal enhancement of approximately 100% immediately after injection, which was sustained largely until 24 hr postinjection. In contrast, the vessel wall of all controls (left carotid artery and animals injected with Gd-DTPA) did not show significant contrast enhancement at those time points. This study demonstrates that intimal thickening in ApoE-KO mice can be effectively detected by contrast-enhanced (CE)-MRI upon injection of paramagnetic liposomes.

Animals↗

PubMed2006

Regional variations in intramyocellular lipid concentration correlate with muscle fiber type distribution in rat tibialis anterior muscle.

1H MR spectroscopy (MRS) has proved to be a valuable noninvasive tool to measure intramyocellular lipids (IMCL) in research focused on insulin resistance and type II diabetes in both humans and rodents. An important determinant of IMCL is the muscle fiber type, since oxidative type I fibers can contain up to three times more IMCL than glycolytic type II muscle fibers. Because these different muscle fiber types are inhomogeneously distributed in rodent muscle, in the present study we investigated the distribution of IMCL within the rat tibialis anterior muscle (TA) in vivo using single-voxel 1H MRS along with the muscle fiber distribution in the TA ex vivo determined from immunohistological assays. IMCL levels in the TA differed by up to a factor of 3 depending on the position of the voxel. The distribution of IMCL over the TA cross section was not random, but emerged in a pattern similar to the distribution of the predominantly oxidative muscle fiber types. Dietary interventions, such as high-fat feeding and 15 hr of fasting, did not significantly change this typical fiber type-dependent pattern of IMCL content. These results stress the importance of voxel positioning when single-voxel 1H MRS is used to study IMCL in rodent muscle.

Animal Feed↗

PubMed2006

DTI-based assessment of ischemia-reperfusion in mouse skeletal muscle.

Diffusion tensor imaging (DTI) is frequently applied to characterize the microscopic geometrical properties of tissue. To establish whether and how diffusion MRI responds to transient ischemia of skeletal muscle, we studied the effects of ischemia and reperfusion using DTI and T2-weighted MRI before and during ischemia and up to 24 hr after reperfusion. Ischemia was induced by 50 min of hindlimb occlusion with or without dorsal flexor stimulation. During ischemia the apparent diffusion coefficient (ADC) tended to decrease (up to 15%), whereas the fractional anisotropy (FA) and T2 showed a varied response depending on the protocol and muscle type. During reperfusion the ADC and T2 initially increased and subsequently renormalized for the occlusion protocol. For the occlusion plus stimulation (OS) protocol, the FA was decreased by 13% and the ADC and T2 were increased by 20% and 57%, respectively, after 24 hr in the stimulated muscle complex. In the latter tissue the three DTI eigenvalues gradually increased upon reperfusion. The smallest eigenvalue (lambda3) showed the largest relative increase. Changes in DTI indices in the reperfusion phases followed a similar time course as the changes in T2. The changes in MR indices after 24 hr correlated with the tissue damage quantified with histology. The highest correlation was observed for lambda3 (R2 = 0.81). This study shows that DTI can be used to assess ischemia-induced damage to skeletal muscle.

Analysis of Variance↗

PubMed2006

Lipid-based nanoparticles for contrast-enhanced MRI and molecular imaging.

In the field of MR imaging and especially in the emerging field of cellular and molecular MR imaging, flexible strategies to synthesize contrast agents that can be manipulated in terms of size and composition and that can be easily conjugated with targeting ligands are required. Furthermore, the relaxivity of the contrast agents, especially for molecular imaging applications, should be very high to deal with the low sensitivity of MRI. Lipid-based nanoparticles, such as liposomes or micelles, have been used extensively in recent decades as drug carrier vehicles. A relatively new and promising application of lipidic nanoparticles is their use as multimodal MR contrast agents. Lipids are amphiphilic molecules with both a hydrophobic and a hydrophilic part, which spontaneously assemble into aggregates in an aqueous environment. In these aggregates, the amphiphiles are arranged such that the hydrophobic parts cluster together and the hydrophilic parts face the water. In the low concentration regime, a wide variety of structures can be formed, ranging from spherical micelles to disks or liposomes. Furthermore, a monolayer of lipids can serve as a shell to enclose a hydrophobic core. Hydrophobic iron oxide particles, quantum dots or perfluorocarbon emulsions can be solubilized using this approach. MR-detectable and fluorescent amphiphilic molecules can easily be incorporated in lipidic nanoparticles. Furthermore, targeting ligands can be conjugated to lipidic particles by incorporating lipids with a functional moiety to allow a specific interaction with molecular markers and to achieve accumulation of the particles at disease sites. In this review, an overview of different lipidic nanoparticles for use in MRI is given, with the main emphasis on Gd-based contrast agents. The mechanisms of particle formation, conjugation strategies and applications in the field of contrast-enhanced, cellular and molecular MRI are discussed.

Contrast Media↗

PubMed2006

Dynamic MRS and MRI of skeletal muscle function and biomechanics.

MR is a powerful technique for studying the biomechanical and functional properties of skeletal muscle in vivo in health and disease. This review focuses on 31P, 1H and 13C MR spectroscopy for assessment of the dynamics of muscle metabolism and on dynamic 1H MRI methods for non-invasive measurement of the biomechanical and functional properties of skeletal muscle. The information thus obtained ranges from the microscopic level of the metabolism of the myocyte to the macroscopic level of the contractile function of muscle complexes. The MR technology presented plays a vital role in achieving a better understanding of many basic aspects of muscle function, including the regulation of mitochondrial activity and the intricate interplay between muscle fiber organization and contractile function. In addition, these tools are increasingly being employed to establish novel diagnostic procedures as well as to monitor the effects of therapeutic and lifestyle interventions for muscle disorders that have an increasing impact in modern society.

Adenosine Triphosphate↗

PubMed2006

Quantum dots with a paramagnetic coating as a bimodal molecular imaging probe.

MRI detectable and targeted quantum dots were developed. To that aim, quantum dots were coated with paramagnetic and pegylated lipids, which resulted in a relaxivity, r(1), of nearly 2000 mM(-1)s(-1) per quantum dot. The quantum dots were functionalized by covalently linking alphavbeta3-specific RGD peptides, and the specificity was assessed and confirmed on cultured endothelial cells. The bimodal character, the high relaxivity, and the specificity of this nanoparticulate probe make it an excellent contrast agent for molecular imaging purposes.

Cells, Cultured↗

PubMed2006

1H MR spectroscopy of the brain: absolute quantification of metabolites.

Hydrogen 1 (1H) magnetic resonance (MR) spectroscopy enables noninvasive in vivo quantification of metabolite concentrations in the brain. Currently, metabolite concentrations are most often presented as ratios (eg, relative to creatine) rather than as absolute concentrations. Despite the success of this approach, it has recently been suggested that relative quantification may introduce substantial errors and can lead to misinterpretation of spectral data and to erroneous metabolite values. The present review discusses relevant methods to obtain absolute metabolite concentrations with a clinical MR system by using single-voxel spectroscopy or chemical shift imaging. Important methodological aspects in an absolute quantification strategy are addressed, including radiofrequency coil properties, calibration procedures, spectral fitting methods, cerebrospinal fluid content correction, macromolecule suppression, and spectral editing. Techniques to obtain absolute concentrations are now available and can be successfully applied in clinical practice. Although the present review is focused on 1H MR spectroscopy of the brain, a large part of the methodology described can be applied to other tissues as well.

Brain↗

PubMed2005

MR molecular imaging and fluorescence microscopy for identification of activated tumor endothelium using a bimodal lipidic nanoparticle.

In oncological research, there is a great need for imaging techniques that specifically identify angiogenic blood vessels in tumors on the basis of differences in the expression level of biomolecular markers. In the angiogenic cascade, different cell surface receptors, including the alphavbeta3-integrin, are strongly expressed on activated endothelial cells. In the present study, we aimed to image angiogenesis by detecting the expression of alphavbeta3 in tumor bearing mice with a combination of magnetic resonance imaging (MRI) and fluorescence microscopy. To that end, we prepared MR-detectable and fluorescent liposomes, which carry approximately 700 alphavbeta3-specific RGD peptides per liposome. RGD competition experiments and RAD-conjugated liposomes were used as controls for specificity. In vivo, both RAD liposomes and RGD liposomes gave rise to signal increase on T1-weighted MR images. It was established by the use of ex vivo fluorescence microscopy that RGD liposomes and RAD liposomes accumulated in the tumor by different mechanisms. RGD liposomes were specifically associated with activated tumor endothelium, while RAD liposomes were located in the extravascular compartment. This study demonstrates that MR molecular imaging of angiogenesis is feasible by using a targeted contrast agent specific for the alphavbeta3-integrin, and that the multimodality imaging approach gave insight into the exact mechanism of accumulation in the tumor.

Animals↗

PubMed2005

Determination of mouse skeletal muscle architecture using three-dimensional diffusion tensor imaging.

Muscle architecture is the main determinant of the mechanical behavior of skeletal muscles. This study explored the feasibility of diffusion tensor imaging (DTI) and fiber tracking to noninvasively determine the in vivo three-dimensional (3D) architecture of skeletal muscle in mouse hind leg. In six mice, the hindlimb was imaged with a diffusion-weighted (DW) 3D fast spin-echo (FSE) sequence followed by the acquisition of an exercise-induced, T(2)-enhanced data set. The data showed the expected fiber organization, from which the physiological cross-sectional area (PCSA), fiber length, and pennation angle for the tibialis anterior (TA) were obtained. The values of these parameters ranged from 5.4-9.1 mm(2), 5.8-7.8 mm, and 21-24 degrees , respectively, which is in agreement with values obtained previously with the use of invasive methods. This study shows that 3D DT acquisition and fiber tracking is feasible for the skeletal muscle of mice, and thus enables the quantitative determination of muscle architecture.

Animals↗

PubMed2005

The effect of B1 field inhomogeneity and the nonselective inversion profile on the kinetics of FAIR-based perfusion MRI.

Perfusion imaging with pulsed arterial spin labeling techniques, like flow-sensitive alternating inversion recovery (FAIR), may suffer from inflow of fresh, i.e., unlabeled, spins. Inflow of fresh spins is caused by the arrival of unlabeled spins in the image slice and can lead to underestimation of the perfusion if not taken into account. In this study it was shown that a decrease in B(1) field strength toward the edge of the transmit coil and the consequent reduction in the inversion efficiency leads to a narrowing of the arterial delivery function and a reduction in FAIR signal. Increasing the B(1) amplitude of the adiabatic inversion pulse from 2.3 to 5.7 times its minimum amplitude requirement resulted in an observed increase of 40 to 80% in the rat brain FAIR signal at inflow times longer than 0.65 s. For coils with limited dimensions and significant B(1) inhomogeneity over the perfusion labeling slab, the application of an excessively large B(1) amplitude in combination with adiabatic inversion is recommended to optimize the FAIR perfusion contrast.

Animals↗

PubMed2005

Intramyocellular lipid content and molecular adaptations in response to a 1-week high-fat diet.

OBJECTIVE: To investigate molecular adaptations that accompany the elevation of intramyocellular lipid (IMCL) content on a high-fat (HF) diet for 1 week. RESEARCH METHODS AND PROCEDURES: Ten subjects consumed a normal-fat (NF) diet for 1 week, followed by an HF diet for another week. After both dietary periods, we determined the IMCL content by proton magnetic resonance spectroscopy in the vastus lateralis muscle and quantified changes in gene expression, protein content, and activity in biopsy samples. We investigated genes involved in carbohydrate and fatty acid handling [lipoprotein lipase, acetyl-coenzyme A carboxylase (ACC) 2, hormone-sensitive lipase, hexokinase II, and glucose transporter 4] and measured protein levels of CD36 and phosphorylated and unphosphorylated ACC2 and the activity of adenosine monophosphate-activated kinase. RESULTS: IMCL content was increased by 54% after the HF period. Lipoprotein lipase mRNA concentration was increased by 33%, whereas ACC2 mRNA concentration tended to be increased after the HF diet. Hexokinase II, glucose transporter 4, and hormone-sensitive lipase mRNA were unchanged after the HF diet. ACC2 and CD36 protein levels, phosphorylation status of ACC2, and adenosine monophosphate-activated kinase activity did not change in response to the HF diet. DISCUSSION: We found that IMCL content in skeletal muscle increased after 1 week of HF feeding, accompanied by molecular adaptations that favor fat storage in muscle rather than oxidation.

Acetyl-CoA Carboxylase↗

PubMed2005

Mitochondrial affinity for ADP is twofold lower in creatine kinase knock-out muscles. Possible role in rescuing cellular energy homeostasis.

Adaptations of the kinetic properties of mitochondria in striated muscle lacking cytosolic (M) and/or mitochondrial (Mi) creatine kinase (CK) isoforms in comparison to wild-type (WT) were investigated in vitro. Intact mitochondria were isolated from heart and gastrocnemius muscle of WT and single- and double CK-knock-out mice strains (cytosolic (M-CK-/-), mitochondrial (Mi-CK-/-) and double knock-out (MiM-CK-/-), respectively). Maximal ADP-stimulated oxygen consumption flux (State3 Vmax; nmol O2 x mg mitochondrial protein(-1) x min(-1)) and ADP affinity (K50ADP; microM) were determined by respirometry. State 3 Vmax and of M-CK-/- and MiM-CK-/- gastrocnemius mitochondria were twofold higher than those of WT, but were unchanged for Mi-CK-/-. For mutant cardiac mitochondria, only the of mitochondria isolated from the MiM-CK-/- phenotype was different (i.e. twofold higher) than that of WT. The implications of these adaptations for striated muscle function were explored by constructing force-flow relations of skeletal muscle respiration. It was found that the identified shift in affinity towards higher ADP concentrations in MiM-CK-/- muscle genotypes may contribute to linear mitochondrial control of the reduced cytosolic ATP free energy potentials in these phenotypes.

Adenosine Diphosphate↗