Quantitative blood flow measurement in rat brain with multiphase arterial spin labelling magnetic resonance imaging

Cerebral blood flow is an important parameter in many diseases and functional studies that can be accurately measured in humans using arterial spin labelling (ASL) MRI. However, although rat models are frequently used for preclinical studies of both human disease and brain function, rat CBF measurements show poor consistency between studies. This lack of reproducibility is due, partly, to the smaller size and differing head geometry of rats compared to humans, as well as the differing analysis methodologies employed and higher field strengths used for preclinical MRI. To address these issues, we have implemented, optimised and validated a multiphase pseudo-continuous ASL technique, which overcomes many of the limitations of rat CBF measurement. Three rat strains (Wistar, Sprague Dawley and Berlin Druckrey IX) were used, and CBF values validated against gold-standard autoradiography measurements. Label positioning was found to be optimal at 45°, while post-label delay was optimised to 0.55 s. Whole brain CBF measures were 109 ± 22, 111 ± 18 and 100 ± 15 mL/100 g/min by multiphase pCASL, and 108 ± 12, 116 ± 14 and 122 ± 16 mL/100 g/min by autoradiography in Wistar, SD and BDIX cohorts, respectively. Tumour model analysis shows that the developed methods also apply in disease states. Thus, optimised multiphase pCASL provides robust, reproducible and non-invasive measurement of CBF in rats

STAT3-mediated astrocyte reactivity associated with brain metastasis contributes to neurovascular dysfunction

© 2020 American Association for Cancer Research. Astrocytes are thought to play a pivotal role in coupling neural activity and cerebral blood flow. However, it has been shown that astrocytes undergo morphologic changes in response to brain metastasis, switching to a reactive phenotype, which has the potential to significantly compromise cerebrovascular function and contribute to the neurological sequelae associated with brain metastasis. Given that STAT3 is a key regulator of astrocyte reactivity, we aimed here to determine the impact of STAT3- mediated astrocyte reactivity on neurovascular function in brain metastasis. Rat models of brain metastasis and ciliary neurotrophic factor were used to induce astrocyte reactivity. Multimodal imaging, electrophysiology, and IHC were performed to determine the relationship between reactive astrocytes and changes in the cerebrovascular response to electrical and physiological stimuli. Subsequently, the STAT3 pathway in astrocytes was inhibited with WP1066 to determine the role of STAT3- mediated astrocyte reactivity, specifically, in brain metastasis. Astrocyte reactivity associated with brain metastases impaired cerebrovascular responses to stimuli at both the cellular and functional level and disrupted astrocyte-endothelial interactions in both animal models and human brain metastasis samples. Inhibition of STAT3-mediated astrocyte reactivity in rats with brain metastases restored cerebrovascular function, as shown by in vivo imaging, and limited cerebrovascular changes associated with tumor growth. Together these findings suggest that inhibiting STAT3-mediated astrocyte reactivity may confer significant improvements in neurological outcome for patients with brain metastases and could potentially be tested in other brain tumors

Neurovascular and neuroimaging effects of the hallucinogenic serotonin receptor agonist psilocin in the rat brain.

The development of pharmacological magnetic resonance imaging (phMRI) has presented the opportunity for investigation of the neurophysiological effects of drugs in vivo. Psilocin, a hallucinogen metabolised from psilocybin, was recently reported to evoke brain region-specific, phMRI signal changes in humans. The present study investigated the effects of psilocin in a rat model using phMRI and then probed the relationship between neuronal and haemodynamic responses using a multimodal measurement preparation. Psilocin (2 mg/kg or 0.03 mg/kg i.v.) or vehicle was administered to rats (N = 6/group) during either phMRI scanning or concurrent imaging of cortical blood flow and recording of local field potentials. Compared to vehicle controls psilocin (2 mg/kg) evoked phMRI signal increases in a number of regions including olfactory and limbic areas and elements of the visual system. PhMRI signal decreases were seen in other regions including somatosensory and motor cortices. Investigation of neurovascular coupling revealed that whilst neuronal responses (local field potentials) to sensory stimuli were decreased in amplitude by psilocin administration, concurrently measured haemodynamic responses (cerebral blood flow) were enhanced. The present findings show that psilocin evoked region-specific changes in phMRI signals in the rat, confirming recent human data. However, the results also suggest that the haemodynamic signal changes underlying phMRI responses reflect changes in both neuronal activity and neurovascular coupling. This highlights the importance of understanding the neurovascular effects of pharmacological manipulations for interpreting haemodynamic neuroimaging data

Covalent assembly of nanoparticles as a peptidase-degradable platform for molecular MRI

© The Author(s) 2017. Ligand-conjugated microparticles of iron oxide (MPIO) have the potential to provide high sensitivity contrast for molecular magnetic resonance imaging (MRI). However, the accumulation and persistence of non-biodegradable micron-sized particles in liver and spleen precludes their clinical use and limits the translational potential of MPIO-based contrast agents. Here we show that ligand-targeted MPIO derived from multiple iron oxide nanoparticles may be coupled covalently through peptide linkers that are designed to be cleaved by intracellular macrophage proteases. The synthesized particles possess potential characteristics for targeted MRI contrast agents, including high relaxivity, unappreciable sedimentation, clearance from circulation and no overt toxicity. Importantly, we demonstrate that these particles are rapidly degraded both in vitro and in vivo, and that the targeted probes can be used for detection of inflammation in vivo using MRI. This approach provides a platform for molecular MRI contrast agents that is potentially more suitable for translation to humans

Sensitivity of Multiphase Pseudocontinuous Arterial Spin Labelling (MP pCASL) Magnetic Resonance Imaging for Measuring Brain and Tumour Blood Flow in Mice

Brain and tumour blood flow can be measured noninvasively using arterial spin labelling (ASL) magnetic resonance imaging (MRI), but reliable quantification in mouse models remains difficult. Pseudocontinuous ASL (pCASL) is recommended as the clinical standard for ASL and can be improved using multiphase labelling (MP pCASL). The aim of this study was to optimise and validate MP pCASL MRI for cerebral blood flow (CBF) measurement in mice and to assess its sensitivity to tumour perfusion. Following optimization of the MP pCASL sequence, CBF data were compared with gold-standard autoradiography, showing close agreement. Subsequently, MP pCASL data were acquired at weekly intervals in models of primary and secondary brain tumours, and tumour microvessel density was determined histologically. MP pCASL measurements in a secondary brain tumour model revealed a significant reduction in blood flow at day 35 after induction, despite a higher density of blood vessels. Tumour core regions also showed reduced blood flow compared with the tumour rim. Similarly, significant reductions in CBF were found in a model of glioma 28 days after tumour induction, together with an increased density of blood vessels. These findings indicate that MP pCASL MRI provides accurate and robust measurements of cerebral blood flow in naïve mice and is sensitive to changes in tumour perfusion

Improved Detection of Molecularly Targeted Iron Oxide Particles in Small Animals with High Resolution MRI

Authors: Paul Kinchesh, Stuart Gilchrist, Niloufar Zarghami, Alexandre A Khrapitchev, Nicola R Sibson, Veerle Kersemans, Sean C Smart. High resolution multi-gradient echo (MGE) scanning is typically used for detection of molecularly targeted iron oxide particles. The images of individual echoes are often combined to generate a composite image with improved SNR from the early echoes and boosted contrast from later echoes. In 3D implementations prolonged scanning at high gradient duty cycles induces a B0 shift that predominantly affects image alignment in the slow phase encoding dimension of 3D MGE images. The effect corrupts the composite echo image and limits the image resolution that is realised. A real-time adaptive B0 stabilisation during respiration gated 3D MGE scanning reduces image misalignment and improves detection of molecularly targeted iron oxide particles in composite images of the mouse brain. Respiration gated MGE 3D scans were performed to visualise molecularly targeted MPIO in a BALB/c mouse model of acute neuroinflammation. Data were acquired with and without B0 stabilisation for comparison. The slow phase encode image dimension runs in the left-right direction of the brain. It is particularly instructive to inspect the registration of image data by selecting an axial slice and scrolling through the acquired echoes. The echoes can be summed to form a simple composite image. The data in this archive demonstrate that high resolution imaging for the detection of molecularly targeted iron oxide particles in the mouse brain requires good stabilisation of the main B0 field so that the composite image resolution reflects the prescribed image resolution. Data were acquired on a 9.4 T 160 mm horizontal bore VNMRS preclinical imaging system equipped with 100 mm bore gradient insert (Varian Inc, CA) and are available for 6 mice. The *.nii files are NIfTI-1 formatted image files, http://nifti.nimh.nih.gov/ ImageJ is a suitable viewer, http://imagej.nih.gov/ij/ M#_compensatedXXX.nii: Mouse #, B0 stabilisation of a XXX Hz frequency drift. M#_uncompensatedYYY.nii: Mouse #, a YYY Hz frequency drift without B0 compensation. # = [1,6

T2-weighted MRI detects presymptomatic pathology in the SOD1 mouse model of ALS

Neuroinflammation has been identified as a potential therapeutic target in amyotrophic lateral sclerosis (ALS), but relevant biomarkers are needed. The superoxide dismutase (SOD1)G93A transgenic mouse model of ALS offers a unique opportunity to study and potentially manipulate presymptomatic pathology. While T2-weighted magnetic resonance imaging (MRI) has been shown to be sensitive to pathologic changes at symptom onset, no earlier biomarkers were previously identified and the underlying histopathologic correlates remain uncertain. To address these issues, we used a multimodal MRI approach targeting structural (T2, T2, apparent diffusion coefficient (ADC), magnetization transfer ratio (MTR)), vascular (gadolinium diethylene triamine pentaacetic acid), and endothelial (vascular cell adhesion molecule-microparticles of iron oxide) changes, together with histopathologic analysis from presymptomatic to symptomatic stages of disease. Presymptomatic changes in brainstem nuclei were evident on T2-weighted images from as early as 60 days (P[less than]0.05). Histologic indices of vacuolation, astro- and microglial activation all correlated with T2-weighted changes. Significant reductions in ADC (P[less than]0.01) and MTR (P[less than]0.05) were found at 120 days in the same brainstem nuclei. No changes in T1 relaxation, vascular permeability, or endothelial activation were found at any stage of disease. These findings suggest that T2-weighted MRI offers the strongest biomarker potential in this model, and that MRI has unique potential for noninvasive and longitudinal assessment of presymptomatically applied therapeutic and neuroprotective agents

What is special about the human arcuate fasciculus? Lateralization, projections, and expansion

Evolutionary adaptations of the human brain are the basis for our unique abilities such as language. An expansion of the arcuate fasciculus (AF), the dorsal language tract, in the human lineage involving left lateralization is considered canonical, but this hypothesis has not been tested in relation to other architectural adaptations in the human brain. Using diffusion-weighted MRI, we examined AF in the human and macaque and quantified species differences in white matter architecture and surface representations. To compare surface results in the two species, we transformed macaque representations to human space using a landmark-based monkey-to-human cortical expansion model. We found that the human dorsal AF, but not the ventral inferior fronto-occipital fasciculus (IFO), is left-lateralized. In the monkey AF is not lateralized. Moreover, compared to the macaque, human AF is relatively increased with respect to IFO. A comparison of human and transformed macaque surface representations suggests that cortical expansion alone cannot account for the species differences in the surface representation of AF. Our results show that the human AF has undergone critical anatomical modifications in comparison with the macaque AF. More generally, this work demonstrates that studies on the human brain specializations underlying the language connectome can benefit from current methodological advances in comparative neuroanatomy.status: publishe