Keywords: CEST / APT / NOE, CEST & MT, data analysis, kinetic modelling, metabolism, brain, cancer

Motivation: While PET, MR spectroscopy, and DGE CEST MRI can describe sugar uptake and utilization using a 2-tissue-compartment model, such a model is not appropriate for DGE CEST MRI of tumors, as the exchange properties of sugar hydroxyl protons may differ between tissue compartments.

Goal(s): To develop a 3-tissue-compartment model (blood, EES and cell) suitable for DGE MRI.

Approach: We modified the mass balance equations and simulated compartmental D-glucose concentrations from D-glucose levels of venous plasma.

Results: The 3-tissue-compartment model was able to reproduce MRS literature brain D-glucose dynamic uptake curves, as well as experimental DGE MRI signal in brain tumors at 7 T.

Impact: A 3-tissue-compartment model is necessary for correct quantification of DGE MRI in malignant brain tumors. Our proposed model is expected to improve modeling and assessment for all metabolic substrate uptake imaging methods in situations of BBB breakdown.

Keywords: Neuroinflammation, Neuroinflammation, blood-brain barrier, vascular-water-exchange imaging, neuromyelitis optica spectrum disorder

Motivation: Limited information exists regarding the spatial characteristics of blood-brain barrier (BBB) disruption at the whole-brain level for neuromyelitis optica spectrum disorder (NMOSD).

Goal(s): We explored spatial features of BBB changes in NMOSD using noninvasive, quantitative MRI technique.

Approach: Vascular-water-exchange MRI was applied for quantitative analysis.

Results: In the white matter, the apparent exchange rate across the BBB (AXR_BBB) was significantly higher in acute-phase patients than in healthy controls, especially in some lesion-prone areas. In the gray matter, acute-phase patients had significantly higher AXR_BBB values in the frontal and parietal lobes. AXR_BBB was also significantly correlated with clinical-scale scores.

Impact: Exploring the spatial features of BBB disruption will enable better understanding the imaging features of NMOSD and may help clinicians in differentially diagnosing NMOSD from other brain diseases using noninvasive MRI.

Keywords: Blood Vessels, Neuro, blood-brain barrier

Motivation: Blood-brain barrier (BBB) water exchange (WEX) imaging techniques are increasingly used to quantify BBB dysfunction. However, WEX imaging is highly noise sensitive, which is typically addressed by averaging data spatially or across subjects. 

Goal(s): To obtain robust, subject-specific, voxel-wise WEX quantification from BBB filter exchange imaging (FEXI) data.

Approach: We implement a hierarchical Bayesian model fitting method, which, by introducing a Gaussian prior for model parameters (estimated from the data), reduces sensitivity to voxel-wise noise. 

Results: Relative to conventional least-squares estimation, Bayesian model fitting improves parameter estimation qualitatively and quantitatively in synthetic and in ten test-retest volunteer datasets.

Impact: Robust, subject-specific, voxel-wise WEX quantification from BBB filter exchange imaging (FEXI) data will enable localised BBB dysfunction to be identified in neurological disease, potentially enabling earlier diagnosis or discrimination between diseases.

Keywords: Alzheimer's Disease, Arterial spin labelling, Blood-brain barrier, Biomarkers

Motivation: Blood-brain barrier (BBB) permeability changes may be implicated in Alzheimer’s Disease (AD) pathophysiology.

Goal(s): To investigate if the exchange time (Tex) of water across the BBB is associated with cognitive and amyloid status.

Approach: We measured Tex with a multi-echo arterial spin labeling MRI sequence in 116 adults older than 50 years and studied its association with cognition (cognitively normal vs mild cognitive impaired) and amyloid (A- vs A+) status.

Results: BBB water permeability is increased in A+ participants and in patients with MCI, compared to healthy controls

Impact: Our results suggest that multi-TE ASL MRI BBB water permeability can be used as a potential early imaging biomarker of AD pathophysiology.

Keywords: Neurofluids, Arterial spin labelling, Blood-brain barrier, Diffusion-weighting

Motivation: Anomalous blood-brain barrier (BBB) water transfer rate (Kw) has the potential to be a novel biomarker for neurological disorders.

Goal(s): However, additional studies are needed to affirm the reliability of MRI sequences that assess Kw.

Approach: This in vivo study sought to determine the intrasession repeatability of the single-delay diffusion-weighted (DW) arterial spin labeling (ASL) MRI sequence at different DW post-label delays (PLDs). [1]

Results: Our findings confirmed that cerebral blood flow (CBF) and Kw were most stable at a DW PLD of 1800ms and that there exists a significant linear correlation between arterial transit time (ATT) and Kw.  

Impact: Our findings show that for single-delay diffusion weighted (DW) ASL MRI, properly selecting the DW PLD and consideration of ATT are crucial for robust BBB water permeability measurements. Studies like ours are necessary before Kw imaging in different disease states.

Keywords: CEST / APT / NOE, CEST & MT, Multiple Sclerosis; CEST enhancement; Dex-Cest

Motivation: Dextrans (Dex) -based CEST MRI allows evaluating vascular permeability in the macromolecular size range. However, its signal intensity, similar to most CEST agents, is pH-dependent, which complicates in vivo quantification.

Goal(s): To develop a dextran CEST agent that is less pH sensitive for this application.

Approach: Chemically modified Dex (CM-Dex) has negatively charged carboxylate groups that can retard the exchange rate of OH protons to decrease pH effects.

Results: CM-Dex has a relatively consistent CEST signal across a pH range of 6 to 7.4 and is feasible for detecting blood-brain barrier (BBB) leakage in a mouse model of multiple sclerosis (MS).

Impact: The development of a second-generation dextran-based CEST agent with a more extended pH range of stable MRI signal to facilitate quantitative measurements of vascular permeability in vivo for applications wherein intra- and inter-individual pH can vary.

Keywords: Simulation/Validation, Quantitative Imaging, Arterial Spin Labeling, Brain, Vessels

Motivation: In diffusion-weighted arterial spin labeling (DW-ASL) images, quantification of the water exchange rate $$$k_{w}$$$ uses a single-pass approximation (SPA) which introduces systematic error while fitting the non-linear model is difficult.  

Goal(s): Our goal was to reduce the blood-brain-barrier (BBB) water exchange rate ($$$k_{w}$$$) quantification errors in DW-ASL images. 

Approach: We introduced the biophysical-modeling-based deep learning method (QTMNet) and tested both the simulated and in vivo data.

Results: On simulated data, QTMNet has 90% less normalized root mean square error (NRMSE) compared to the traditional kinetic model. 

Impact: The improvement in evaluation accuracy by QTMNet may benefit Alzheimer’s Disease detection where $$$k_{w}$$$ has significant reduction.

Keywords: Diagnosis/Prediction, Perfusion, DCE-MRI, Glioblastoma, Blood-brain barrier, Deep learning, Generative adversarial networks

Motivation: Arterial input function (AIF) in DCE-MRI is often degraded due to noise, motion, and partial volume. This may lower the overall reliability of the resulting pharmacokinetic (PK) parameters.

Goal(s): Our goal was to develop a robust, fast method for detecting blood-brain barrier (BBB) leakage signals without PK models.

Approach: We employed a fast anomaly detection using generative adversarial networks (f-AnoGAN) for unsupervised detection of the leakage signals.

Results: The results were highly correlated with the traditional K^trans maps, and more robust against reduced temporal data points, which may be used for shorter scan time and/or higher spatial resolution.

Impact: Our proposed method may allow fast and robust detection of BBB leakage signals in the case where the scan time is highly limited, and consequently, the traditional approach with PK models may not be suitable.

Keywords: Data Processing, DSC & DCE Perfusion, Blood Brain Barrier, NESMA filtering, subtle BBB permeability

Motivation: Recently, Dynamic Contrast-Enhanced MRI studies revealed increased Blood-Brain Barrier (BBB) permeability in aging and in Alzheimer’s disease (AD). However, the subtle BBB disruption in aging and in AD yields substantially low contrast extravasation, which results in an intrinsically low signal-to-noise ratio. 

Goal(s): An effective filtering method is desirable to suppress noise, while maintaining the spatial variation in contrast dynamics.

Approach: We propose an iterative nonlocal estimation of multispectral magnitudes (iNESMA) filtering approach, which achieves noise-filtering by combining the voxels with similar spectral patterns. 

Results: Our results suggest that iNESMA filtering allows accurate and precise determination of kinetic parameters for subtle BBB permeability.

Impact: We propose an effective, yet straightforward, filtering paradigm for improved determination of the kinetic parameters from DCE-MR images. Our proposed iNESMA filtering would allow better characterization of subtle vascular changes in aging and in AD.

Keywords: Neurofluids, Neurofluids, Glymphatic

Motivation: Aquaporin-4 (AQP4) water channels are thought to play an important role in cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange. However, the effect of AQP4 on CSF drainage and dynamics has not been well-established.

Goal(s): To investigate the effects of AQP4 on CSF drainage and dynamics using in vivo imaging.

Approach: We performed a whole-brain analysis including CSF spaces and drainage pathways of AQP4 knockout rats using dynamic contrast-enhanced (DCE) MRI with intrathecal gadolinium-based contrast agent administration.

Results: DCE-MRI showed that loss of AQP4 impairs solute clearance from the CSF space and reduces CSF-ISF exchange.

Impact: Loss of AQP4 impairs CSF-ISF exchange as well as solute clearance from the CSF space, suggesting that AQP4 expression might affect the entire CSF dynamics.  

Keywords: Neuroinflammation, Cancer, chemotherapy, treatment, late effects, pediatric, development

Motivation: Doxorubicin (DXR) is a widely used chemotherapy agent associated with inflammation and neurocognitive impairment in cancer survivors. Given that DXR has limited access to the brain, indirect mechanisms, such as the generation of systemic pro-inflammatory cytokines, are proposed to induce neurotoxicity and neuroinflammation.

Goal(s): This study aims to probe this hypothesized pro-inflammatory pathway of DXR-induced neurotoxicity.

Approach: We identified an elevation of the pro-inflammatory cytokine IL-6 in DXR-treated mice. Consequently, we utilized MRI to assess neuroanatomical changes after DXR treatment in wildtype and Il-6 knockout mice.

Results: Our findings revealed that Il-6 knockout partially mitigated the neurotoxic effects induced by DXR.

Impact: DXR leads to cognitive impairment that diminishes quality of life for cancer survivors. We demonstrated the involvement of IL-6 in the neurotoxic mechanism of DXR, suggesting a strategy for targeting IL-6 to limit neurotoxicity of cancer treatments.

Keywords: Multiple Sclerosis, Multiple Sclerosis, Brain Lymphatics

Motivation: Multiple sclerosis (MS) involves a proinflammatory state leading to cellular waste accumulation and disability. This study investigates the glymphatic system's waste clearance role, hypothesizing that lymphatic dysfunction contributes to MS-related disability.

Goal(s): Explore the relationship between glymphatic function, meningeal lymphatic vessels (mLV), and MS-related disability.

Approach: The study examined 49 MS patients using MRI to visualize mLVs and evaluate glymphatic stasis via CSF fraction (CSFF), analyzing links between mLV volume, CSFF, and MS outcomes

Results: With age, cortical CSFF increases. mLV volume also increases with CSFF. Higher cortical CSFF is associated with more lesions and disability, suggesting glymphatic dysfunction contributes to MS-related disability.

Impact: Our study suggests that glymphatic dysfunction contributes to lesion burden and disability in multiple sclerosis, highlighting the importance of lymphatic clearance mechanisms in disease progression.

Keywords: Neuroinflammation, Radiotherapy, 1H MRS

Motivation: Cognitive performance in paediatrics is severely impacted by current brain tumour treatment plans such as radiotherapy. 

Goal(s): Our goal is to decipher the underlying mechanism of this cognitive decline, which remains unknown and is particularly difficult to decipher in paediatric patients due to confounding developmental variables. 

Approach: Longitudinal ¹H MRS analysis in the brain following radiotherapy in a juvenile rat model provides valuable insight into metabolic disruption.

Results: Myo-inositol levels, linked to other neurodegenerative and cognitive conditions, were elevated in the hippocampus and cerebellum. Deviance in N-acetyl-aspartate levels between irradiated and healthy rats over a developmental period of 12.5 weeks was also revealed.

Impact: ¹H MR spectroscopy reveals valuable insight into longitudinal impacts of radiotherapy on the developing brain. A juvenile rat model enables acute and chronic alterations in inflammatory markers, membrane synthesis, bioenergetics and viability to be monitored, distinguishing irradiation and development effects.

Keywords: Epilepsy, Neuroinflammation, anti-NMDAR, Spectroscopy, rCBV

Motivation: The chronic phase of autoimmune encephalitis includes persistent loss of cognitive and adaptive functions leading to long-term disability. MR-based modalities help in longitudinal studies to understand disease progression and response to treatment.

Goal(s): To investigate the in vivo MRI-based methods sensitive to detecting the alterations in metabolites and perfusion in encephalitis patients.

Approach: ¹H-MRS and rCBV were performed on encephalitis patients with memory deficits and healthy controls.  

Results: Changes in metabolite concentrations in the hippocampus and cortex suggest the long-term effect of neuroinflammation in patients. Reduced hippocampal rCBV in memory deficit patients is consistent with clinical cognitive assessments.   

Impact: Altered brain metabolite concentrations and regional blood volume were detected with ¹H-MRS and rCBV in autoimmune encephalitis and memory deficit patients. This approach can support the investigation of the role of angiogenesis and neurogenesis in memory loss in chronic encephalitis.

Keywords: Digestive, Infectious disease

Motivation: Neural alterations affect intestinal conditions. However, these neural alterations and their potential formation mechanisms remain unclear.

Goal(s): We integrated brain radiomics, the fecal microbiome, and blood metabolomics to investigate neural characteristics in patients with Crohn’s disease (CD) by establishing putative links between the gut microbiota, blood metabolites, and brain alterations.

Approach: Multiomics data were compared between CD patients and healthy controls. 

Results: We developed a novel multiparameter brain MRI-based radiomics model to characterize the neural features of CD patients. Causal mediation analysis revealed significant pathways supporting the pivotal role of the gut-brain axis in neural alterations in CD patients.

Impact: We developed a novel multiparameter MRI-based radiomics model to comprehensively characterize neural alterations in patients with Crohn’s disease. We presented biologically plausible evidence of the formation mechanism underlying these alterations from a gut-microbiota-brain axis perspective.

Keywords: Infectious Disease, Infectious disease, cerebral malaria

Motivation: Artesunate is the first-line treatment of P. falciparum malaria. However, despite artesunate therapy, there is a 15% fatality rate in severe malaria and survivors can suffer long-term neurocognitive deficits. 

Goal(s): Describe the evolving pathology in experimental cerebral malaria (ECM) model treated with artesunate, to develop a model for testing adjunctive therapy in cerebral malaria.

Approach: In vivo MRI was applied on ECM mice prior to and post artesunate treatment.

Results: Despite rapid clearance of the parasite by artesunate, significantly reduced CBF and subsequent reperfusion/reoxygenation injury is detected by MRI, and may ultimately cause neurocognitive deficits in CM survivors.

Impact: It is critical to understand the evolving pathology after antimalarial cure with artesunate in cerebral malaria in order to design effective adjunctive therapy, to reduce mortality and neurocognitive impairment. Reduced CBF and its rapid recovery may contribute to CM neuropathology.

Keywords: Infectious Disease, Diffusion/other diffusion imaging techniques, HIV

Motivation: People with HIV and co-morbid severe depression are rarely included in research, despite a critical need for identifying biomarkers for early detection of depression in this group. 

Goal(s): We explored whether neuroimaging biomarkers may distinguish between people with HIV experiencing severe or mild depressive symptoms.

Approach: We recruited 11 participants with HIV and severe or mild depressive symptoms, who underwent standard and diffusion-weighted MR spectroscopy and dynamic contrast-enhanced MRI.

Results: We found no significant group differences, but observed correlations of depressive symptom severity with creatine (ρ = 0.66) and NAA (ρ = 0.64) diffusion, though these findings did not survive multiple comparisons correction.

Impact: This is the first study to successfully quantify neurometabolite diffusion in people with HIV and depression. Intracellular diffusion of neurometabolites may be associated with depressive symptom severity in this community, and well-powered studies are needed to resolve this relationship.

Keywords: Infectious Disease, Brain Connectivity, fMRI (task-based), High-Field MRI

Motivation: To assess Functional Connectivity (FC) differences between healthy individuals and Myalgic Encephalomyelitis or chronic fatigue syndrome (ME/CFS) patients using ultra-high-field fMRI.

Goal(s): Are there significant FC differences between brainstem and cerebellum regions comparing ME/CFS and healthy controls? Is there any association between clinical measures and FC in ME/CFS?

Approach: fMRI data were acquired on 7Tesla scanner during cognitive Stroop color-word task. Using a-priori regions, FC was assessed in CONN toolbox.

Results: Weaker FC was observed between brainstem and cerebellum regions along with altered FC within the intrinsic network hubs which supports our hypothesis of connectivities being defective in ME/CFS within those regions.

Impact: FC analyses using ultra-high-field MRI facilitates our understanding of the underlying patho-mechanisms of the cognitive deficits in ME/CFS and their progression.

Keywords: Alzheimer's Disease, Alzheimer's Disease

Motivation: BBB disruption is demonstrated in Alzheimer’s disease (AD) but how does it change during the progression of disease, and its relationship with transcytolemmal water exchange are not clear.

Goal(s): We aimed to evaluate the longitudinal changes of water exchange across BBB and across cytomembrane in AD mice.

Approach: BBB permeability and transcytolemmal permeability to water were assessed in 3xTg-AD mouse from 6 to 10 months of age using WEPCAST and tDKI MRI, respectively.

Results: Elevation of BBB permeability in AD mice started as early as 6 months. Transcytolemmal permeability was found to increase in the hippocampus.

Impact: Current results suggested the potential role of BBB and transcytolemmal permeability as a biomarker in the early detection of AD. Their co-increase may be related to the altered glymphatic function.

Keywords: White Matter, White Matter, FLAIR, harmonization, white matter hyperintensity

Motivation: Harmonizing neural imaging datasets respectively acquired with 2D and 3D FLAIR MRI.

Goal(s): Converting 2D FLAIRs to high-resolution 3D FLAIRs.

Approach: We employed a ResUNet-based deep learning approach to learn the complex transformation from 2D to 3D FLAIR.

Results: The converted 3D FLAIRs bear a high resemblance to the acquired 3D FLAIR in terms of image similarity measures and white matter hyperintensity segmentation. 

Impact: With this proposed approach, we can harmonize the 2D FLAIRs from the ADNI study with the 3D FLAIRs in the UK Biobank study.