Developing blood-brain barrier arterial spin labelling as a non-invasive early biomarker of Alzheimer's disease (DEBBIE-AD): a prospective observational multicohort study protocol.

INTRODUCTION: Loss of blood-brain barrier (BBB) integrity is hypothesised to be one of the earliest microvascular signs of Alzheimer's disease (AD). Existing BBB integrity imaging methods involve contrast agents or ionising radiation, and pose limitations in terms of cost and logistics. Arterial spin labelling (ASL) perfusion MRI has been recently adapted to map the BBB permeability non-invasively. The DEveloping BBB-ASL as a non-Invasive Early biomarker (DEBBIE) consortium aims to develop this modified ASL-MRI technique for patient-specific and robust BBB permeability assessments. This article outlines the study design of the DEBBIE cohorts focused on investigating the potential of BBB-ASL as an early biomarker for AD (DEBBIE-AD). METHODS AND ANALYSIS: DEBBIE-AD consists of a multicohort study enrolling participants with subjective cognitive decline, mild cognitive impairment and AD, as well as age-matched healthy controls, from 13 cohorts. The precision and accuracy of BBB-ASL will be evaluated in healthy participants. The clinical value of BBB-ASL will be evaluated by comparing results with both established and novel AD biomarkers. The DEBBIE-AD study aims to provide evidence of the ability of BBB-ASL to measure BBB permeability and demonstrate its utility in AD and AD-related pathologies. ETHICS AND DISSEMINATION: Ethics approval was obtained for 10 cohorts, and is pending for 3 cohorts. The results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal.

Subject-specific timing adaption in time-encoded arterial spin labeling imaging.

OBJECTIVES: One challenge in arterial spin labeling (ASL) is the high variability of arterial transit times (ATT), which causes associated arterial transit delay (ATD) artifacts. In patients with pathological changes, these artifacts occur when post-labeling delay (PLD) and bolus durations are not optimally matched to the subject, resulting in difficult quantification of cerebral blood flow (CBF) and ATT. This is also true for the free lunch approach in Hadamard-encoded pseudocontinuous ASL (H-pCASL). MATERIAL AND METHODS: Five healthy volunteers were scanned with a 3 T MR-system. pCASL-subbolus timing was adjusted individually by the developed adaptive Walsh-ordered pCASL sequence and an automatic feedback algorithm. The quantification results for CBF and ATT and the respective standard deviations were compared with results obtained using recommended timings and intentionally suboptimal timings. RESULTS: The algorithm individually adjusted the pCASL-subbolus PLD for each subject within the range of recommended timing for healthy subjects, with a mean intra-subject adjustment deviation of 47.15 ms for single-shot and 44.5 ms for segmented acquisition in three repetitions. DISCUSSION: A first positive assessment of the results was performed on healthy volunteers. The extent to which the results can be transferred to patients and are of benefit must be investigated in follow-up studies.

Reliability of multi-site UK Biobank MRI brain phenotypes for the assessment of neuropsychiatric complications of SARS-CoV-2 infection: The COVID-CNS travelling heads study.

INTRODUCTION: Magnetic resonance imaging (MRI) of the brain could be a key diagnostic and research tool for understanding the neuropsychiatric complications of COVID-19. For maximum impact, multi-modal MRI protocols will be needed to measure the effects of SARS-CoV-2 infection on the brain by diverse potentially pathogenic mechanisms, and with high reliability across multiple sites and scanner manufacturers. Here we describe the development of such a protocol, based upon the UK Biobank, and its validation with a travelling heads study. A multi-modal brain MRI protocol comprising sequences for T1-weighted MRI, T2-FLAIR, diffusion MRI (dMRI), resting-state functional MRI (fMRI), susceptibility-weighted imaging (swMRI), and arterial spin labelling (ASL), was defined in close approximation to prior UK Biobank (UKB) and C-MORE protocols for Siemens 3T systems. We iteratively defined a comparable set of sequences for General Electric (GE) 3T systems. To assess multi-site feasibility and between-site variability of this protocol, N = 8 healthy participants were each scanned at 4 UK sites: 3 using Siemens PRISMA scanners (Cambridge, Liverpool, Oxford) and 1 using a GE scanner (King's College London). Over 2,000 Imaging Derived Phenotypes (IDPs), measuring both data quality and regional image properties of interest, were automatically estimated by customised UKB image processing pipelines (S2 File). Components of variance and intra-class correlations (ICCs) were estimated for each IDP by linear mixed effects models and benchmarked by comparison to repeated measurements of the same IDPs from UKB participants. Intra-class correlations for many IDPs indicated good-to-excellent between-site reliability. Considering only data from the Siemens sites, between-site reliability generally matched the high levels of test-retest reliability of the same IDPs estimated in repeated, within-site, within-subject scans from UK Biobank. Inclusion of the GE site resulted in good-to-excellent reliability for many IDPs, although there were significant between-site differences in mean and scaling, and reduced ICCs, for some classes of IDP, especially T1 contrast and some dMRI-derived measures. We also identified high reliability of quantitative susceptibility mapping (QSM) IDPs derived from swMRI images, multi-network ICA-based IDPs from resting-state fMRI, and olfactory bulb structure IDPs from T1, T2-FLAIR and dMRI data. CONCLUSION: These results give confidence that large, multi-site MRI datasets can be collected reliably at different sites across the diverse range of MRI modalities and IDPs that could be mechanistically informative in COVID brain research. We discuss limitations of the study and strategies for further harmonisation of data collected from sites using scanners supplied by different manufacturers. These acquisition and analysis protocols are now in use for MRI assessments of post-COVID patients (N = 700) as part of the ongoing COVID-CNS study.

Concordance of regional hypoperfusion by pCASL MRI and 15O-water PET in frontotemporal dementia: Is pCASL an efficacious alternative?

BACKGROUND: Clinical diagnosis of frontotemporal dementia (FTD) remains a challenge due to the overlap of symptoms among FTD subtypes and with other psychiatric disorders. Perfusion imaging by arterial spin labeling (ASL) is a promising non-invasive alternative to established PET techniques; however, its sensitivity to imaging parameters can hinder its ability to detect perfusion abnormalities. PURPOSE: This study evaluated the similarity of regional hypoperfusion patterns detected by ASL relative to the gold standard for imaging perfusion, PET with radiolabeled water (15O-water). METHODS AND MATERIALS: Perfusion by single-delay pseudo continuous ASL (SD-pCASL), free-lunch Hadamard encoded pCASL (FL_TE-pCASL), and 15O-water data were acquired on a hybrid PET/MR scanner in 13 controls and 9 FTD patients. Cerebral blood flow (CBF) by 15O-water was quantified by a non-invasive approach (PMRFlow). Regional hypoperfusion was determined by comparing individual patients to the control group. This was performed using absolute (aCBF) and CBF normalized to whole-brain perfusion (rCBF). Agreement was assessed based on the fraction of overlapping voxels. Sensitivity and specificity of pCASL was estimated using hypoperfused regions of interest identified by 15O-water. RESULTS: Region of interest (ROI) based perfusion measured by 15O-water strongly correlated with SD-pCASL (R = 0.85 ± 0.1) and FL_TE-pCASL (R = 0.81 ± 0.14). Good agreement in terms of regional hypoperfusion patterns was found between 15O-water and SD-pCASL (sensitivity = 70%, specificity = 78%) and between 15O-water and FL_TE-pCASL (sensitivity = 71%, specificity = 73%). However, SD-pCASL showed greater overlap (43.4 ± 21.3%) with 15O-water than FL_TE-pCASL (29.9 ± 21.3%). Although aCBF and rCBF showed no significant differences regarding spatial overlap and metrics of agreement with 15O-water, rCBF showed considerable variability across subtypes, indicating that care must be taken when selecting a reference region. CONCLUSIONS: This study demonstrates the potential of pCASL for assessing regional hypoperfusion related to FTD and supports its use as a cost-effective alternative to PET.

Combined acquisition of diffusion and T2*-weighted measurements using simultaneous multi-contrast magnetic resonance imaging.

OBJECT: In this work, we present a technique called simultaneous multi-contrast imaging (SMC) to acquire multiple contrasts within a single measurement. Simultaneous multi-slice imaging (SMS) shortens scan time by allowing the repetition time (TR) to be reduced for a given number of slices. SMC imaging preserves TR, while combining different scan types into a single acquisition. This technique offers new opportunities in clinical protocols where examination time is a critical factor and multiple image contrasts must be acquired. MATERIALS AND METHODS: High-resolution, navigator-corrected, diffusion-weighted imaging was performed simultaneously with T2*-weighted acquisition at 3 T in a phantom and in five healthy subjects using an adapted readout-segmented EPI sequence (rs-EPI). RESULTS: The results demonstrated that simultaneous acquisition of two contrasts (here diffusion-weighted imaging and T2*-weighting) with SMC imaging is feasible with robust separation of contrasts and minimal effect on image quality. DISCUSSION: The simultaneous acquisition of multiple contrasts reduces the overall examination time and there is an inherent registration between contrasts. By using the results of this study to control saturation effects in SMC, the method enables rapid acquisition of distortion-matched and well-registered diffusion-weighted and T2*-weighted imaging, which could support rapid diagnosis and treatment of acute stroke.

Sensitivity of Arterial Spin Labeling for Characterization of Longitudinal Perfusion Changes in Frontotemporal Dementia and Related Disorders.

BACKGROUND: Advances in the understanding of the pathophysiology of frontotemporal dementia (FTD) and related disorders, along with the development of novel candidate disease modifying treatments, have stimulated the need for tools to assess the efficacy of new therapies. While perfusion imaging by arterial spin labeling (ASL) is an attractive approach for longitudinal imaging biomarkers of neurodegeneration, sources of variability between sessions including arterial transit times (ATT) and fluctuations in resting perfusion can reduce its sensitivity. Establishing the magnitude of perfusion changes that can be reliably detected is necessary to delineate longitudinal perfusion changes related to disease processes from the effects of these sources of error. PURPOSE: To assess the feasibility of ASL for longitudinal monitoring of patients with FTD by quantifying between-session variability of perfusion on a voxel-by-voxel basis. METHODS AND MATERIALS: ASL data were collected in 13 healthy controls and 8 patients with FTD or progressive supra-nuclear palsy. Variability in cerebral blood flow (CBF) by single delay pseudo-continuous ASL (SD-pCASL) acquired one month apart were quantified by the coefficient of variation (CV) and intraclass correlation coefficient (ICC). Additionally, CBF by SD-pCASL and ATT by low-resolution multiple inversion time ASL (LowRes-pCASL) were compared to Hadamard encoded sequences which are able to simultaneously measure CBF and ATT with improved time-efficiency. RESULTS: Agreement of grey-matter perfusion between sessions was found for both patients and controls (CV = 10.8% and 8.3% respectively) with good reliability for both groups (ICC > 0.6). Intensity normalization to remove day-to-day fluctuations in resting perfusion reduced the CV by 28%. Less than 5% of voxels had ATTs above the chosen post labelling delay (2 s), indicating that the ATT was not a significant source of error. Hadamard-encoded perfusion imaging yielded systematically higher CBF compared to SD-pCASL, but produced similar transit-time measurements. Power analysis revealed that SD-pCASL has the sensitivity to detect longitudinal changes as low as 10% with as few as 10 patient participants. CONCLUSION: With the appropriate labeling parameters, SD-pCASL is a promising approach for assessing longitudinal changes in CBF associated with FTD.

Deep Learning for Ultrasound Image Formation: CUBDL Evaluation Framework and Open Datasets.

Deep learning for ultrasound image formation is rapidly garnering research support and attention, quickly rising as the latest frontier in ultrasound image formation, with much promise to balance both image quality and display speed. Despite this promise, one challenge with identifying optimal solutions is the absence of unified evaluation methods and datasets that are not specific to a single research group. This article introduces the largest known international database of ultrasound channel data and describes the associated evaluation methods that were initially developed for the challenge on ultrasound beamforming with deep learning (CUBDL), which was offered as a component of the 2020 IEEE International Ultrasonics Symposium. We summarize the challenge results and present qualitative and quantitative assessments using both the initially closed CUBDL evaluation test dataset (which was crowd-sourced from multiple groups around the world) and additional in vivo breast ultrasound data contributed after the challenge was completed. As an example quantitative assessment, single plane wave images from the CUBDL Task 1 dataset produced a mean generalized contrast-to-noise ratio (gCNR) of 0.67 and a mean lateral resolution of 0.42 mm when formed with delay-and-sum beamforming, compared with a mean gCNR as high as 0.81 and a mean lateral resolution as low as 0.32 mm when formed with networks submitted by the challenge winners. We also describe contributed CUBDL data that may be used for training of future networks. The compiled database includes a total of 576 image acquisition sequences. We additionally introduce a neural-network-based global sound speed estimator implementation that was necessary to fairly evaluate the results obtained with this international database. The integration of CUBDL evaluation methods, evaluation code, network weights from the challenge winners, and all datasets described herein are publicly available (visit https://cubdl.jhu.edu for details).

Deep learning-based reconstruction of ultrasound images from raw channel data.

PURPOSE: We investigate the feasibility of reconstructing ultrasound images directly from raw channel data using a deep learning network. Starting from the raw data, we present the network the full measurement information, allowing for a more generic reconstruction to form, as compared to common reconstructions constrained by physical models using fixed speed of sound assumptions. METHODS: We propose a U-Net-like architecture for the given task. Additional layers with strided convolutions downsample the raw data. Hyperparameter optimization was used to find a suitable learning rate. We train and test our deep learning approach on plane wave ultrasound images with a single insonification angle. The dataset includes phantom as well as in vivo data. RESULTS: The images produced by our method are visually comparable to ones reconstructed with the conventional delay and sum algorithm. Deviations between prediction and ground truth are likely to be related to speckle noise. For the test set, the mean absolute error is [Formula: see text] for the phantom images and [Formula: see text] for the in vivo data. CONCLUSION: The result shows the feasibility of our approach and opens up new research directions regarding information retrieval from raw channel data. As the networks reconstruction performance is limited by the quality of the ground truth images, using other ultrasound reconstruction technique or image types as target data would be of interest.

Simultaneous multislice acquisition with multi-contrast segmented EPI for separation of signal contributions in dynamic contrast-enhanced imaging.

We present a method to efficiently separate signal in magnetic resonance imaging (MRI) into a base signal S0, representing the mainly T1-weighted component without T2*-relaxation, and its T2*-weighted counterpart by the rapid acquisition of multiple contrasts for advanced pharmacokinetic modelling. This is achieved by incorporating simultaneous multislice (SMS) imaging into a multi-contrast, segmented echo planar imaging (EPI) sequence to allow extended spatial coverage, which covers larger body regions without time penalty. Simultaneous acquisition of four slices was combined with segmented EPI for fast imaging with three gradient echo times in a preclinical perfusion study. Six female domestic pigs, German-landrace or hybrid-form, were scanned for 11 minutes respectively during administration of gadolinium-based contrast agent. Influences of reconstruction methods and training data were investigated. The separation into T1- and T2*-dependent signal contributions was achieved by fitting a standard analytical model to the acquired multi-echo data. The application of SMS yielded sufficient temporal resolution for the detection of the arterial input function in major vessels, while anatomical coverage allowed perfusion analysis of muscle tissue. The separation of the MR signal into T1- and T2*-dependent components allowed the correction of susceptibility related changes. We demonstrate a novel sequence for dynamic contrast-enhanced MRI that meets the requirements of temporal resolution (Δt < 1.5 s) and image quality. The incorporation of SMS into multi-contrast, segmented EPI can overcome existing limitations of dynamic contrast enhancement and dynamic susceptibility contrast methods, when applied separately. The new approach allows both techniques to be combined in a single acquisition with a large spatial coverage.