Mark F. Lythgoe

Purpose: We developed a dynamic, heavily T2‐weighted (hT2w) FLAIR protocol to resolve acute Mn ²⁺ transport kinetics, as a proxy for Ca ²⁺ , across the choroid plexus (ChP)—cerebrospinal fluid (CSF) interface, in vivo. By quantifying intercompartmental Mn ²⁺ dynamics, and comparing these with Gd‐DOTA, we sought to characterize blood‐CSF‐barrier (BCSFB)‐mediated tracer transport, combining high in‐plane resolution and 4‐min temporal sampling. Methods: hT2w‐FLAIR DCE MRI was conducted in anesthetized C57BL/6 mice, receiving intravenous Mn ²⁺ or Gd‐DOTA. Semi‐quantitative tracer kinetic modeling permitted regional and inter‐tracer comparisons. Results: Mn ²⁺ rapidly crossed from the vasculature into the CSF, across the ChP, with similar arrival times and time‐to‐peak across compartments. Mn ²⁺ delivery into the ChP exhibited a 5.7‐fold steeper uptake rate ( p = 0.031) and a 5.6‐fold higher peak signal amplitude ( p = 0.0028) than in the LV‐CSF. In contrast, Gd‐DOTA exhibited a 2.2‐fold shorter ChP plateau duration ( p = 0.034) and 2.2‐fold faster ChP clearance rate ( p = 0.0047), compared to Mn ²⁺ . Within the CSF, there were significant temporal delays with Gd‐DOTA relative to Mn ²⁺ : a lengthened arrival (eight‐fold, p = 0.045) and time‐to‐peak (six‐fold, p = 0.024). Conclusion: Our hT2w‐FLAIR DCE‐MRI approach captured the early BCSFB transport window for Mn ²⁺ , providing distinct ChP and LV‐CSF kinetics at a higher temporal resolution and with reduced CSF signal contamination compared to prior approaches. These findings highlight that MRI tracer choice strongly shapes measured BCSFB kinetics, and supports the use of Mn ²⁺ as a tool for probing compartment‐specific ChP transport.

Microplastics are posing an escalating threat to both ecological systems and human health. Yet, current methods for investigating their bioaccumulation are highly invasive, requiring destructive analysis of ex vivo tissues via mass spectrometry, dye labelling, or Raman microspectroscopy. This limits the study of biodistribution dynamics in preclinical models and human populations, leaving an urgent need for non‐invasive alternatives. Meeting this challenge, for the first time in living tissue, the native optical absorption properties of microplastics are exploited to generate photoacoustic signal – imageable ultrasound emission following thermalisation of pulsed laser light. Distinct optical absorption profiles enable microplastic differentiation from endogenous biological signal sources, long‐term tracking over 2 months in a mouse model, and microscale resolution of particle features verified histologically. This novel approach overcomes previous limitations of optical and nuclear imaging methods relying on fluorescent dyes or radio‐isotopes, going beyond small transparent organisms such as zebrafish or nematodes, and half‐life‐dependent timescales, respectively. By enabling serial monitoring of microplastic biodistribution dynamics, this technique will help interrogate interacting factors such as ingestion route, microplastic shape, size and polymer type – and their effects on accumulation, degradation, clearance, and disease in animal models, and, ultimately, human subjects.

Glioblastoma (GBM) is the most common and aggressive brain tumour with stark resistance to available therapies, leading to relapse and a median survival of <15 months. A key cause of therapy resistance is diffuse infiltration of tumour cells into brain regions surrounding the tumour, which presents a major clinical challenge as existing imaging techniques offer limited detection of the resectable margin. Here, we use diffusion weighted imaging (DWI) and apply the multiple echo time neurite orientation dispersion and density imaging (MTE-NODDI) model as a tool to detect tumour cells in the hard-to-distinguish margin. We used the G144 patient-derived xenograft model, with characteristic invasion along white matter tracts, in combination with MTE-NODDI. Tumour development was monitored, and magnetic resonance imaging (MRI) data were acquired over a 4-week period, starting at 4 weeks after stereotactic injection of tumour cells. MTE-NODDI demonstrated sensitivity to the developing tumour in the invading margin, and changes in measured parameters were apparent from 6 weeks after injection. In comparison to standard DWI, MTE-NODDI showed increased sensitivity to the tumour-associated changes in the margin. Furthermore, extraneurite volume fraction (fen) and neurite density index (NDI) measured from MTE-NODDI correlated with immunohistological measurement of tumour cells. These findings suggest that MTE-NODDI may non-invasively detect infiltrating cells and tumour-induced pathology in margin regions without T2 or DWI changes in a patient-derived mouse model of GBM. MTE-NODDI is clinically translatable and could be a powerful tool for neurosurgeons to maximise surgical resection, resulting in better survival outcomes for patients with GBM.

Propagation and aggregation of prion proteins, such as tau and α-synuclein (αSyn), are key pathological features of neurodegenerative diseases. Extracellular clearance pathways, such as the glymphatic system, may play a crucial role in the removal of these toxic proteins from the brain. Primarily active during sleep, this system relies on aquaporin-4 (AQP4) water channel expression and polarisation to astrocytic endfeet, facilitating interstitial solute clearance. Glymphatic dysfunction has recently been implicated in Parkinson’s disease, however the precise mechanisms underlying the pathogenic effect of this dysfunction remain unclear. This includes how impaired glymphatic function influences αSyn propagation dynamics, and the role of propagating αSyn itself on glymphatic function. In this study, we used a mouse model of αSyn propagation to elucidate the impact of αSyn aggregation on glymphatic function, by measuring CSF-ISF exchange and assessing AQP4 and associated endfoot complex proteins in the brain over time and across different regions. Our results show that direct injection of αSyn pre-formed fibrils leads to reduced expression of the AQP4 endfoot complex, but propagation of endogenous αSyn induces an enhancement of glymphatic function suggesting compensatory upregulation in response to increasing endogenous αSyn load. To determine the influence of glymphatic dysfunction on αSyn propagation dynamics, we then employed a pharmacological approach to inhibit glymphatic function in this model. Acute glymphatic inhibition significantly reduced brain to CSF αSyn clearance, and chronic treatment exacerbated αSyn pathology, neurodegeneration, and motor behavioural deficits in mice. Together our findings show that αSyn clearance and propagation are modulated by glymphatic function and suggest that AQP4 complex dysregulation may contribute to glymphatic impairment associated with Parkinson’s diseases. Summary for the non-scientific community The glymphatic system clears brain waste during sleep. Lopes et al. show that α-synuclein, a protein linked to Parkinson’s, is cleared by this system. Using a mouse model of the disease, they suggest that aquaporin-4 water channels may impair glymphatic function, contributing to α-synuclein buildup in patients’ brains.

Magnetic field hyperthermia relies on the intra-tumoural delivery of magnetic nanoparticles by interstitial injection, followed by their heating on exposure to a remotely-applied alternating magnetic field (AMF). This offers a potential sole or adjuvant route to treating drug-resistant tumours for which no alternatives are currently available. However, two challenges in nanoparticle delivery currently hinder the effective clinical translation of this technology: obtaining enough magnetic material within the tumour to enable sufficient heating; and doing this accurately to limit or avoid damage to surrounding healthy tissue. A further complication is the lack of established methods to non-invasively quantify nanoparticle biodistribution, which is necessary to evaluate the performance of improved delivery strategies. Here we employ ¹¹¹In radiolabelling and single-photon emission computed tomography (SPECT) to non-invasively quantify distribution of a clinical grade iron-oxide-based nanoparticle in a mouse model of melanoma. We show that compared to manual injection, ultrasound guided delivery together with syringe-pump-controlled infusion improves both the nanoparticle concentration within the tumour, and the accuracy of delivery – reducing off-target peri-tumoural delivery. Following AMF heating, injected melanomas shrank significantly compared to non-injected controls, validating therapeutic efficacy. Systemic off-target delivery was quantified and extrapolated to predict off-target energy absorbance within safe limits for the main sites of background accumulation. With many nanoparticle-based therapies currently in development for cancer, this image-guided delivery strategy has wide potential impact beyond the field of magnetic hyperthermia. Future use in representative patient cohorts would also be enabled by the high clinical availability of both SPECT and ultrasound imaging.

Hallmarks of autosomal dominant polycystic kidney disease (ADPKD), the most common hereditary kidney anomaly, include expanding fluid-filled epithelial cysts, inflammation, and fibrosis. Despite previous work showing the potential of vascular-based therapies, renal microvascular alterations in ADPKD, and their timing, are poorly understood. Using single-cell transcriptomics of human kidney microvasculature, we identify a population of endothelial cells adjacent to cysts in ADPKD. This pericystic endothelium, distinguishable by its expression of osteopontin (SPP1), has a distinct molecular profile compared to the common endothelial cell injury signature in other kidney diseases. SPP1 ⁺ pericystic endothelium was also present in an orthologous mouse model of ADPKD before overt kidney functional decline. By interrogating geometric, topological and fractal properties from three-dimensional imaging of early ADPKD mouse kidneys, we show that pericystic endothelium associates with disorganisation and non-uniformity of the renal cortical microvasculature. Concurrently, we detected region-specific reductions in cortical blood flow within ADPKD murine kidneys using arterial spin labelling. We conclude that ADPKD kidneys contain a unique subset of endothelium manifesting with aberrant remodelling and impaired blood perfusion. Its detection, prior to renal functional decline, advocates the vasculature as a therapeutic target to modulate or preserve renal function in early ADPKD.

Mathematical oncology provides unique and invaluable insights into tumour growth on both the microscopic and macroscopic levels. This review presents state-of-the-art modelling techniques and focuses on their role in understanding glioblastoma, a malignant form of brain cancer. For each approach, we summarize the scope, drawbacks and assets. We highlight the potential clinical applications of each modelling technique and discuss the connections between the mathematical models and the molecular and imaging data used to inform them. By doing so, we aim to prime cancer researchers with current and emerging computational tools for understanding tumour progression. By providing an in-depth picture of the different modelling techniques, we also aim to assist researchers who seek to build and develop their own models and the associated inference frameworks. Our article thus strikes a unique balance. On the one hand, we provide a comprehensive overview of the available modelling techniques and their applications, including key mathematical expressions. On the other hand, the content is accessible to mathematicians and biomedical scientists alike to accommodate the interdisciplinary nature of cancer research.

Medical therapies achieve their control at expense to the patient in the form of a range of toxicities, which incur costs and diminish quality of life. Magnetic resonance navigation is an emergent technique that enables image‐guided remote‐control of magnetically labeled therapies and devices in the body, using a magnetic resonance imaging (MRI) system. Minimally INvasive IMage‐guided Ablation (MINIMA), a novel, minimally invasive, MRI‐guided ablation technique, which has the potential to avoid traditional toxicities, is presented. It comprises a thermoseed navigated to a target site using magnetic propulsion gradients generated by an MRI scanner, before inducing localized cell death using an MR‐compatible thermoablative device. The authors demonstrate precise thermoseed imaging and navigation through brain tissue using an MRI system (0.3 mm), and they perform thermoablation in vitro and in vivo within subcutaneous tumors, with the focal ablation volume finely controlled by heating duration. MINIMA is a novel theranostic platform, combining imaging, navigation, and heating to deliver diagnosis and therapy in a single device.

Astrocytes play crucial and diverse roles in brain health and disease. The ability to selectively control astrocytes provides a valuable tool for understanding their function and has the therapeutic potential to correct dysfunction. Existing technologies such as optogenetics and chemogenetics require the introduction of foreign proteins, which adds a layer of complication and hinders their clinical translation. A novel technique, magnetomechanical stimulation (MMS), that enables remote and selective control of astrocytes without genetic modification is described here. MMS exploits the mechanosensitivity of astrocytes and triggers mechanogated Ca²⁺ and adenosine triphosphate (ATP) signaling by applying a magnetic field to antibody‐functionalized magnetic particles that are targeted to astrocytes. Using purpose‐built magnetic devices, the mechanosensory threshold of astrocytes is determined, a sub‐micrometer particle for effective MMS is identified, the in vivo fate of the particles is established, and cardiovascular responses are induced in rats after particles are delivered to specific brainstem astrocytes. By eliminating the need for device implantation and genetic modification, MMS is a method for controlling astroglial activity with an improved prospect for clinical application than existing technologies.

The glymphatic system, that is aquaporin 4 (AQP4) facilitated exchange of CSF with interstitial fluid (ISF), may provide a clearance pathway for protein species such as amyloid-β and tau, which accumulate in the brain in Alzheimer’s disease. Further, tau protein transference via the extracellular space, the compartment that is cleared by the glymphatic pathway, allows for its neuron-to-neuron propagation, and the regional progression of tauopathy in the disorder. The glymphatic system therefore represents an exciting new target for Alzheimer’s disease. Here we aim to understand the involvement of glymphatic CSF-ISF exchange in tau pathology. First, we demonstrate impaired CSF-ISF exchange and AQP4 polarization in a mouse model of tauopathy, suggesting that this clearance pathway may have the potential to exacerbate or even induce pathogenic accumulation of tau. Subsequently, we establish the central role of AQP4 in the glymphatic clearance of tau from the brain; showing marked impaired glymphatic CSF-ISF exchange and tau protein clearance using the novel AQP4 inhibitor, TGN-020. As such, we show that this system presents as a novel druggable target for the treatment of Alzheimer’s disease, and possibly other neurodegenerative diseases alike.