Nicola R Sibson

University of Oxford | OX · Department of Oncology

Aims According to Braak's hypothesis, it is plausible that Parkinson's disease (PD) originates in the enteric nervous system (ENS) and spreads to the brain through the vagus nerve. In this work, we studied whether inflammatory bowel diseases (IBDs) in humans can progress with the emergence of pathogenic α‐synuclein (α‐syn) in the gastrointestinal t...

Understanding brain structure and function often requires combining data across different modalities and scales to link microscale cellular structures to macroscale features of whole brain organisation. Here we introduce the BigMac dataset, a resource combining in vivo MRI, extensive postmortem MRI and multi-contrast microscopy for multimodal chara...

Brain metastasis is responsible for a large proportion of cancer mortality, and there are currently no effective treatments. Moreover, the impact of treatments, particularly anti-angiogenic therapeutics, is difficult to ascertain using current magnetic resonance imaging (MRI) methods. Imaging of the angiogenic vasculature has been successfully carr...

Brain metastasis is responsible for a large proportion of cancer mortality, and there are currently no effective treatments. Moreover, the impact of treatments, particularly anti-angiogenic therapeutics, is difficult to ascertain using current magnetic resonance imaging (MRI) methods. Imaging of the angiogenic vasculature has been successfully carr...

Understanding brain structure and function often requires combining data across different modalities and scales to link microscale cellular structures to macroscale features of whole brain organisation. Here we introduce the BigMac dataset, a resource combining in vivo MRI, extensive postmortem MRI and multi-contrast microscopy for multimodal chara...

Purpose: Despite optimal local therapy, tumor cell invasion into normal brain parenchyma frequently results in recurrence in patients with solid tumors. The aim of this study was to determine whether microvascular inflammation can be targeted to better delineate the tumor-brain interface through vascular cell adhesion molecule-1 (VCAM-1)-targeted...

Breast cancer brain metastasis is a significant clinical problem and carries a poor prognosis. Although it is well-established that macrophages are a primary component of the brain metastasis microenvironment, the role of blood-derived macrophages (BDM) and brain-resident microglia in the progression of brain metastases remains uncertain. The aim o...

Purpose In chemical exchange saturation transfer imaging, saturation effects between −2 to −5 ppm (nuclear Overhauser effects, NOEs) have been shown to exhibit contrast in preclinical stroke models. Our previous work on NOEs in human stroke used an analysis model that combined NOEs and semisolid MT; however their combination might feasibly have red...

Purpose: Early diagnosis of cancer is critical for improving patient outcomes, but cancers may be hard to diagnose if patients present with nonspecific signs and symptoms. We have previously shown that nuclear magnetic resonance (NMR) metabolomics analysis can detect cancer in animal models and distinguish between differing metastatic disease burde...

Brain metastases (BM) are frequently detected during the follow-up of patients with malignant tumors, particularly in those with advanced disease. Despite a major progress in systemic anti-cancer treatments, the average overall survival of these patients remains limited (6 months from diagnosis). Also, cognitive decline is regularly reported especi...

Background Metastasis to the brain is a major challenge with poor prognosis. The blood-brain barrier (BBB) is a significant impediment to effective treatment, being intact during the early stages of tumor development and heterogeneously permeable at later stages. Intravenous injection of tumor necrosis factor (TNF) selectively induces BBB permeabil...

Lung cancer patients frequently develop brain metastases (BM). Despite aggressive treatment including neurosurgery and external-radiotherapy, overall survival remains poor. There is a pressing need to further characterize factors in the microenvironment of BM that may confer resistance to radiotherapy (RT), such as hypoxia. Here, hypoxia was first...

The BigMac dataset is a unique resource that includes extensive MRI and densely sampled microscopy data acquired in a single, whole macaque brain. However, the high-resolution microscopy currently only informs on the fibre orientations in the 2D plane of sampled slides, precluding 3D reconstruction of the microscopy connectome. Here we use precise...

Ultrasound and microbubbles (MBs) offer a noninvasive method of temporarily enhancing blood–brain barrier (BBB) permeability to therapeutics. To reduce off‐target effects, it is desirable to minimize the ultrasound pressures required. It has been shown that a new formulation of MBs containing lysolipids (Lyso‐MBs) can increase the cellular uptake o...

Purpose To assess the correlation and differences between common amide proton transfer (APT) quantification methods in the diagnosis of ischemic stroke. Methods Five APT quantification methods, including asymmetry analysis and its variants as well as two Lorentzian model‐based methods, were applied to data acquired from six rats that underwent mid...

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...

Intra-axonal axial diffusivity could be interesting biomarker of disease, yet it is often assumed constant across the white matter. Furthermore, when intra-axonal diffusivity is estimated, few models account for fibre orientation dispersion which (when not explicitly modelled) will greatly affect the estimates of axial diffusion. Here we combine th...

White matter (WM) plasticity during adulthood is a recently described phenomenon by which experience can shape brain structure. It has been observed in humans using diffusion tensor imaging (DTI) and myelination has been suggested as a possible mechanism. Here, we set out to identify molecular and cellular changes associated with WM plasticity meas...

Purpose: Brain metastases are almost universally lethal with short median survival times. Despite this, they are often potentially curable, with therapy failing only because of local relapse. One key reason relapse occurs is because treatment planning did not delineate metastasis margins sufficiently or accurately, allowing residual tumor to regro...

Purpose: 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 g...

Purpose Targeted alpha therapy (TAT) takes advantage of the short‐range and high‐linear energy transfer of α‐particles and is increasingly used, especially for the treatment of metastatic lesions. Nevertheless, dosimetry of α‐emitters is challenging for the very same reasons, even for in vitro experiments. Assumptions, such as the uniformity of the...

The interactions of anterior temporal structures, and especially the amygdala, with the prefrontal cortex are pivotal to learning, decision-making, and socio-emotional regulation. A clear anatomical description of the organization and dissociation of fiber bundles linking anterior temporal cortex/amygdala and prefrontal cortex in humans is still la...

Circulating extracellular vesicles (EVs) regulate signaling pathways via receptor-ligand interactions and content delivery, after attachment or internalization by endothelial cells. However, they originate from diverse cell populations and are heterogeneous in composition. To determine the effects of specific surface molecules, the use of synthetic...

Metastatic tumours in the brain now represent one of the leading causes of death from cancer. Current treatments are largely ineffective due the combination of late diagnosis and poor delivery of chemotherapy across the blood brain barrier (BBB). They are also associated with significant side effects due to lack of specificity. Conjugating MRI cont...

Background: Brain metastases (BM) develop frequently in patients with breast cancer. Despite the use of external beam radiotherapy (EBRT), the average overall survival is short (6 months from diagnosis). The therapeutic challenge is to deliver molecularly targeted therapy at an early stage when relatively few metastatic tumour cells have invaded t...

Translocator protein (TSPO) expression is increased in activated glia, and has been used as a marker of neuroinflammation in PET imaging. However, the extent to which TSPO upregulation reflects a pro- or anti-inflammatory phenotype remains unclear. Our aim was to determine whether TSPO upregulation in astrocytes and microglia/macrophages is limited...

The role of Notch signaling and its ligand JAGGED1 (JAG1) in tumor biology has been firmly established, making them appealing therapeutic targets for cancer treatment. Here, we report the development and characterization of human/rat-specific JAG1-neutralizing mAbs. Epitope mapping identified their binding to the Notch receptor interaction site wit...

Purpose Multi‐phase PCASL has been proposed as a means to achieve accurate perfusion quantification that is robust to imperfect shim in the labeling plane. However, there exists a bias in the estimation process that is a function of noise in the data. In this work, this bias is characterized and then addressed in animal and human data. Methods The...

Detailing the development of HIUFU: High Intensity Un-Focused Ultrasound and its potential for treating widespread disease. Pre-clinical success of this technique is shown.

This study investigates the effect of microbubbles containing lysolipids (lyso-MBs) on cell-cell tight junction opening and cell membrane permeabilisation in vitro, then takes these findings forward to investigate the effect of lyso-MBs on ultrasound mediated blood-brain barrier disruption (US-BBBD). Quantitative fluoresence microscopy techniques...

Diffusion MRI has the ability to reveal the complex connectivity of the human brain. However, the link between the diffusion signal and the underlying tissue microstructure remains elusive. To drive diffusion MRI validation, we present BigMac: a unique dataset which combines ultra-high angular resolution diffusion MRI with microscopy throughout an...

The interactions between amygdala and prefrontal cortex are pivotal to many neural processes involved in learning, decision-making, emotion, and social regulation. The broad functional role of amygdala-prefrontal interplay may reflect the diversity of its anatomical connections. Little, however, is known of the structural wiring linking amygdala an...

White matter (WM) plasticity during adulthood is a recently described phenomenon by which experience can shape brain structure. It has been observed in humans using diffusion tensor imaging (DTI). However, it remains unclear which mechanisms drive or underlie WM plasticity in adulthood. Here, we combined DTI and mRNA expression analysis and examine...

Abnormal pH is a common feature of malignant tumors and has been associated clinically with suboptimal outcomes. Amide proton transfer magnetic resonance imaging (APT MRI) holds promise as a means to noninvasively measure tumor pH, yet multiple factors collectively make quantification of tumor pH from APT MRI data challenging. The purpose of this s...

The permeabilisation of cell membranes when exposed to ultrasound (US) and microbubbles (MBs) has considerable potential for improving therapeutic delivery, and similar mechanisms are thought to underlie ultrasound mediated blood brain barrier disruption (US-BBBD). Recent studies have demonstrated that transfer of material takes place between phosp...

Purpose: A major issue for the effective treatment of brain metastasis is the late stage of diagnosis with existing clinical tools. The aim of this study was to evaluate the potential of vascular cell adhesion molecule 1 (VCAM-1)-targeted MRI for early detection of brain micrometastases in mouse models across multiple primary tumor types. Experimen...

Integrating Dy-DOTA motifs into mesoporous silica nanoparticle scaffolds generates remarkable ultrahigh field T2 relaxivities for a well-defined and tailorable contrast agent, attributed to enhanced Curie outer-sphere contributions and supported by...

Brain and tumour blood flow can be measured non-invasively using arterial spin labelling (ASL) magnetic resonance imaging (MRI), but reliable quantification in mouse models remains difficult. Pseudo-continuous ASL (pCASL) is recommended as the clinical standard for ASL, and can be improved using multiphase labelling (MP pCASL). The aim of this stud...

Purpose: A major issue for the effective treatment of brain metastasis is the late stage of diagnosis with existing clinical tools. The aim of this study was to evaluate the potential of vascular cell adhesion molecule 1 (VCAM-1)-targeted MRI for early detection of brain micrometastases in mouse models across multiple primary tumor types.Experimen...

The immune landscape in brain metastasis is a very heterogeneous framework. Amongst a broad plethora of cells within the tumor microenvironment, the presence of activated microglia has been perfectly described. The innate role of microglial cells is to detect and eliminate any insults that may disturb the regular behavior of the brain. As part of i...

Hyperpolarised MRI with Dynamic Nuclear Polarisation overcomes the fundamental thermodynamic limitations of conventional magnetic resonance, and is translating to human studies with several early-phase clinical trials in progress including early reports that demonstrate the utility of the technique to observe lactate production in human brain cance...

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Metastatic tumors in the brain represent one of the leading causes of death from cancer with current treatments being largely ineffective and/or associated with significant side effects due to their lack of targeting. Conjugating MRI contrast agents with a monoclonal antibody for VCAM1 (anti-VCAM1) has previously allowed detection of brain tumor vo...

Background Molecular MRI is an evolving field of research with strong translational potential. Selection of the appropriate MRI sequence, field strength and contrast agent depend largely on the application. The primary aims of the current study were to: 1) assess the sensitivity of different MRI sequences for detection of iron oxide particles in mo...

Positive control Prussian blue staining for USPIO and counterstaining with nuclear fast red. Notes: (A) Mouse liver section, blue: USPIO; pink: nuclei, (B) Mouse spleen section, blue: USPIO; pink: nuclei. Abbreviation: USPIO, ultra-small superparamagnetic iron oxide.

Particle size distribution (intensity-weighted) of VCAM-USPIO measured by DLS. Note: The 3 traces are repeated measurements of the same sample. Abbreviations: DLS, dynamic light scattering; USPIO, ultra-small superparamagnetic iron oxide; VCAM, vascular cell adhesion molecule.

(A) MPIO (top row) and USPIO (bottom row) were embedded in 2% agarose gel at the same iron concentration (triplicates). (A–C): 0.2 mM, (D–F): 0.1 mM, (G–I): 0.05 mM, (J–L): 0.024 mM, and (M–O): PBS. T2 (ms) and R2 (Hz) maps generated at 7.0 T are shown. (B) T2 relaxivity was measured for both particles; MPIO showed significantly greater relaxivity...

Metastatic tumors in the brain represent one of the leading causes of death from cancer with current treatments being largely ineffective and/or associated with significant side effects due to their lack of targeting. Conjugating MRI contrast agents with a monoclonal antibody for VCAM1 (anti-VCAM1) has previously allowed detection of brain tumor vo...

Introduction Angiogenesis is an important marker of tumour stage and aggressiveness. Many anti-angiogenic therapies exist, although clinical success remains poor partly due to difficulties in patient selection. Molecular magnetic resonance imaging (MRI) using targeted microparticles of iron oxide (MPIO) has been used to image angiogenic vessels in...

Model-based analysis of CEST MRI is a robust quantitative method, however, the lengthy acquisition and processing times make it less clinically feasible. It has recently been proposed that partial acquisition of Z-spectra provides a faster approach, but at the cost of increased variability and large alterations in baseline Amide Proton Transfer (AP...

Comparing the brains of related species faces the challenges of establishing homologies whilst accommodating evolutionary specializations. Here we propose a general framework for understanding similarities and differences between the brains of primates. The approach uses white matter blueprints of the whole cortex based on a set of white matter tra...

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 b...

Microbubbles are currently in clinical use as ultrasound contrast agents and under active investigation as mediators of ultrasound therapy. To improve the theranostic potential of microbubbles, nanoparticles can be attached to the bubble shell for imaging, targeting and/or enhancement of acoustic response. Existing methods for fabricating particle-...

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 l...

BACKGROUND Malignant melanoma frequently metastasises to the brain, with between 10% to 40% of patients estimated to develop intracranial metastases following diagnosis. Although treatments are available for managing brain metastases, their frequently late stage of detection limits the therapeutic potential. Anti-VCAM-1 antibody conjugated micropar...

Comparing the brains of related species faces the challenges of establishing homologies whilst accommodating evolutionary specializations. Here we propose a general framework for understanding similarities and differences between the brains of primates. The approach uses white matter blueprints of the whole cortex based on a set of white matter tra...

Brain metastases develop frequently in patients with breast cancer, and present a pressing therapeutic challenge. Expression of vascular cell adhesion molecule 1 (VCAM-1) is upregulated on brain endothelial cells during the early stages of metastasis and provides a target for the detection and treatment of early brain metastases. The aim of this st...

The overlapping clinical features of relapsing remitting multiple sclerosis (RRMS), aquaporin-4 (AQP4)-antibody (Ab) neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein (MOG)-Ab disease mean that detection of disease specific serum antibodies is the gold standard in diagnostics. However, antibody levels are not p...

Brain metastasis is a common complication of cancer patients and is associated with poor survival. Histological data from patients with brain metastases suggest that microglia are the major immune population activated around the metastatic foci. Microglia and macrophages have the ability to polarize to different phenotypes and to exert both tumorig...

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pdf

The purpose of this study was to explore changes in the CEST signal in the ischaemic core associated with nuclear Overhauser effects (NOEs) and semisolid MT in the context of clinical imaging of hyperacute stroke, using a robust model-fitting scheme that tries to separate downfield CEST contributions.

Ischaemic stroke is a life-threatening condition where part of the brain becomes cut off from a supply of blood causing irreversible brain damage within hours. Recent studies have found that the nuclear Overhauser effect (NOE) region of the spectrum exhibits contrast in preclinical stroke models. A previous clinical demonstration of NOEs in acute h...

Model-based analysis of APT MRI has been shown to quantitatively outperform conventional approaches such as asymmetry analysis. However clinical application is hindered by slow acquisition of whole z-spectra, and processing times. Here, we demonstrate that by using only a subset of frequency offsets, acquisition and processing time can be reduced b...

Microbubbles are currently in clinical use as ultrasound contrast agents and under active investigation as mediators of ultrasound therapy. To improve the theranostic potential of microbubbles, nanoparticles can be attached to the bubble shell for imaging, targeting and/or enhancement of acoustic response. Existing methods for fabricating particle-...

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 cont...

MRI of mouse injected intracerebrally with Il-1b and intravenously with aVCAMAF488-mMPIO. Serial in vivo T2*-weighted coronal images of mouse brain taken from a 3D gradient echo data set with ~90 mm isotropic resolution. This mouse received intrastriatal injection of 20 ng IL-1b in 1 ml saline 3 h prior to intravenous injection of aVCAM-AF488-mMPIO...

Supplementary Figures, Supplementary Tables, Supplementary Note, Supplementary Methods and Supplementary References

Particle degradation by macrophages. Time-course montage of particle degradation by the murine macrophage cell line RAW264.7 obtained by live-cell confocal imaging. Fluorescent particle degradation was imaged over 12 hours taking an image every 2 minutes, during which time the number of visible particles decreased markedly.

MRI of mouse injected intracerebrally with Il-1b and intravenously with IgGAF488-mMPIO. Serial in vivo T2*-weighted coronal images of mouse brain taken from a 3D gradient echo data set with ~90 mm isotropic resolution. This mouse also received intrastriatal injection of 20 ng IL-1b in 1 ml saline 3 h prior to intravenous injection of IgG-AF488-mMPI...

Significance statement: Neuronal activity leads to the generation of CO2, which has previously been shown to evoke cerebral blood flow (CBF) increases via the release of the vasodilator PgE2 We demonstrate that hypercapnia (increased CO2) evokes increases in astrocyte calcium signaling which in turn stimulates COX-1 activity and generates downstre...

Brain metastasis is a common complication of breast cancer patients with poor survival. Histological analysis of autopsy samples from patients with brain metastases suggests that microglia, rather than lymphocytes, are the major immune population activated around the metastatic foci (1). Microglia and macrophages are versatile immune cells with the...

Molecular imaging with probes targeting integrin avb3 have shown promise in imaging angiogenesis in subcutaneous tumours across different modalities. However, brain metastases have been shown to grow co-optively along the existing vasculature in the early stages of development, and do not exhibit angiogenesis until later stages. This angiogenic swi...

OBJECTIVES: Over 20% of cancer patients develop brain metastases. Current MRI diagnostic techniques only detect late stage metastases, since they rely on blood-brain-barrier permeability to allow contrast enhancement. Thus, new methods enabling earlier diagnosis are urgently needed. We have previously shown that it is possible to discriminate betwe...

Brain perfusion imaging can contribute valuable information in diseases such as cancer and stroke. Arterial spin labelling (ASL) is a non-invasive MRI technique enabling quantification of perfusion by imaging tissue following exchanges of water with magnetically tagged blood. Although ASL has recently been standardised in the clinic1, pre-clinical...

The presence of an intact, impermeable blood-brain barrier (BBB) during the early (micrometastatic) stages of tumour development limits significantly both early detection and effective treatment of brain metastasis. Systemic administration of tumour necrosis factor (TNF) in murine models has been shown to transiently permeabilise the BBB selectivel...

Manuel Sarmiento Soto, James R. Larkin, Kleopatra Andreou, Ana Dominguez Bajo, Christina Simoglou Karali and Nicola R. Sibson. Cancer Research UK & Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, UK. The most common cause of cancer demise is the metastasis to distant organs. In particu...

We compared the course and cortical projections of white matter fibers passing through the extreme capsule in humans and macaques. Previous comparisons of this tract have suggested a uniquely human posterior projection, but these studies have always employed different techniques in the different species. Here we used the same technique, diffusion M...