Reproducibility of 3 T APT-CEST in Healthy Volunteers and Patients With Brain Glioma

BACKGROUND: Amide proton transfer (APT) imaging is a chemical exchange saturation transfer (CEST) technique offering potential clinical applications such as diagnosis, characterization, and treatment planning and monitoring in glioma patients. While APT-CEST has demonstrated high potential, reproducibility remains underexplored. PURPOSE: To investigate whether cerebral APT-CEST with clinically feasible scan time is reproducible in healthy tissue and glioma for clinical use at 3 T. STUDY TYPE: Prospective, longitudinal. SUBJECTS: Twenty-one healthy volunteers (11 females; mean age ± SD: 39 ± 11 years) and 6 glioma patients (3 females; 50 ± 17 years: 4 glioblastomas, 1 oligodendroglioma, 1 radiologically suspected low-grade glioma). FIELD STRENGTH/SEQUENCE: 3 T, Turbo Spin Echo - ampling perfection with application optimized contrasts using different flip angle evolution - chemical exchange saturation transfer (TSE SPACE-CEST). ASSESSMENT: APT-CEST measurement reproducibility was assessed within-session (glioma patients, scan session 1; healthy volunteers scan sessions 1, 2, and 3), between-sessions (healthy volunteers scan sessions 1 and 2), and between-days (healthy volunteers, scan sessions 1 and 3). The mean APTCEST values and standard deviation of the within-subject difference (SDdiff ) were calculated in whole tumor enclosed by regions of interest (ROIs) in patients, and eight ROIs in healthy volunteers-whole-brain, cortical gray matter, putamen, thalami, orbitofrontal gyri, occipital lobes, central brain-and compared. STATISTICAL TESTS: Brown-Forsythe tests and variance component analysis (VCA) were used to assess the reproducibility of ROIs for the three time intervals. Significance was set at P  P > 0.22). The within-session SDdiff of whole-brain was 0.2% in both healthy volunteers and patients, and 0.21% in the segmented tumor. VCA showed that within-session factors were the most important (60%) for scanning variance. DATA CONCLUSION: Cerebral APT-CEST imaging may show good scan-rescan reproducibility in healthy tissue and tumors with clinically feasible scan times at 3 T. Short-term measurement effects may be the dominant components for reproducibility. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2

Imaging blood-brain barrier dysfunction: A state-of-the-art review from a clinical perspective

The blood-brain barrier (BBB) consists of specialized cells that tightly regulate the in- and outflow of molecules from the blood to brain parenchyma, protecting the brain's microenvironment. If one of the BBB components starts to fail, its dysfunction can lead to a cascade of neuroinflammatory events leading to neuronal dysfunction and degeneration. Preliminary imaging findings suggest that BBB dysfunction could serve as an early diagnostic and prognostic biomarker for a number of neurological diseases. This review aims to provide clinicians with an overview of the emerging field of BBB imaging in humans by answering three key questions: (1. Disease) In which diseases could BBB imaging be useful? (2. Device) What are currently available imaging methods for evaluating BBB integrity? And (3. Distribution) what is the potential of BBB imaging in different environments, particularly in resource limited settings? We conclude that further advances are needed, such as the validation, standardization and implementation of readily available, low-cost and non-contrast BBB imaging techniques, for BBB imaging to be a useful clinical biomarker in both resource-limited and well-resourced settings

Genetic, vascular, and amyloid components of cerebral blood flow in a preclinical population

Aging-related cognitive decline can be accelerated by a combination of genetic factors, cardiovascular and cerebrovascular dysfunction, and amyloid-β burden. Whereas cerebral blood flow (CBF) has been studied as a potential early biomarker of cognitive decline, its normal variability in healthy elderly is less known. In this study, we investigated the contribution of genetic, vascular, and amyloid-β components of CBF in a cognitively unimpaired (CU) population of monozygotic older twins. We included 134 participants who underwent arterial spin labeling (ASL) MRI and [18F]flutemetamol amyloid-PET imaging at baseline and after a four-year follow-up. Generalized estimating equations were used to investigate the associations of amyloid burden and white matter hyperintensities with CBF. We showed that, in CU individuals, CBF: 1) has a genetic component, as within-pair similarities in CBF values were moderate and significant (ICC > 0.40); 2) is negatively associated with cerebrovascular damage; and 3) is positively associated with the interaction between cardiovascular risk scores and early amyloid-β burden, which may reflect a vascular compensatory response of CBF to early amyloid-β accumulation. These findings encourage future studies to account for multiple interactions with CBF in disease trajectory analyses

Imaging blood-brain barrier dysfunction: A state-of-the-art review from a clinical perspective

The blood-brain barrier (BBB) consists of specialized cells that tightly regulate the in- and outflow of molecules from the blood to brain parenchyma, protecting the brain’s microenvironment. If one of the BBB components starts to fail, its dysfunction can lead to a cascade of neuroinflammatory events leading to neuronal dysfunction and degeneration. Preliminary imaging findings suggest that BBB dysfunction could serve as an early diagnostic and prognostic biomarker for a number of neurological diseases. This review aims to provide clinicians with an overview of the emerging field of BBB imaging in humans by answering three key questions: (1. Disease) In which diseases could BBB imaging be useful? (2. Device) What are currently available imaging methods for evaluating BBB integrity? And (3. Distribution) what is the potential of BBB imaging in different environments, particularly in resource limited settings? We conclude that further advances are needed, such as the validation, standardization and implementation of readily available, low-cost and non-contrast BBB imaging techniques, for BBB imaging to be a useful clinical biomarker in both resource-limited and well-resourced settings

Reproducibility of arterial spin labeling cerebral blood flow image processing:A report of the ISMRM open science initiative for perfusion imaging (OSIPI) and the ASL MRI challenge

Purpose: Arterial spin labeling (ASL) is a widely used contrast-free MRI method for assessing cerebral blood flow (CBF). Despite the generally adopted ASL acquisition guidelines, there is still wide variability in ASL analysis. We explored this variability through the ISMRM-OSIPI ASL-MRI Challenge, aiming to establish best practices for more reproducible ASL analysis. Methods: Eight teams analyzed the challenge data, which included a high-resolution T1-weighted anatomical image and 10 pseudo-continuous ASL datasets simulated using a digital reference object to generate ground-truth CBF values in normal and pathological states. We compared the accuracy of CBF quantification from each team's analysis to the ground truth across all voxels and within predefined brain regions. Reproducibility of CBF across analysis pipelines was assessed using the intra-class correlation coefficient (ICC), limits of agreement (LOA), and replicability of generating similar CBF estimates from different processing approaches. Results: Absolute errors in CBF estimates compared to ground-truth synthetic data ranged from 18.36 to 48.12 mL/100 g/min. Realistic motion incorporated into three datasets produced the largest absolute error and variability between teams, with the least agreement (ICC and LOA) with ground-truth results. Fifty percent of the submissions were replicated, and one produced three times larger CBF errors (46.59 mL/100 g/min) compared to submitted results. Conclusions: Variability in CBF measurements, influenced by differences in image processing, especially to compensate for motion, highlights the significance of standardizing ASL analysis workflows. We provide a recommendation for ASL processing based on top-performing approaches as a step toward ASL standardization.</p

Reproducibility of arterial spin labeling cerebral blood flow image processing: a report of the ISMRM open science initiative for perfusion imaging (OSIPI) and the ASL MRI challenge

Purpose: Arterial spin labeling (ASL) is a widely used contrast-free MRI method for assessing cerebral blood flow (CBF). Despite the generally adopted ASL acquisition guidelines, there is still wide variability in ASL analysis. We explored this variability through the ISMRM-OSIPI ASL-MRI Challenge, aiming to establish best practices for more reproducible ASL analysis. Methods: Eight teams analyzed the challenge data, which included a high-resolution T1-weighted anatomical image and 10 pseudo-continuous ASL datasets simulated using a digital reference object to generate ground-truth CBF values in normal and pathological states. We compared the accuracy of CBF quantification from each team's analysis to the ground truth across all voxels and within predefined brain regions. Reproducibility of CBF across analysis pipelines was assessed using the intra-class correlation coefficient (ICC), limits of agreement (LOA), and replicability of generating similar CBF estimates from different processing approaches. Results: Absolute errors in CBF estimates compared to ground-truth synthetic data ranged from 18.36 to 48.12 mL/100 g/min. Realistic motion incorporated into three datasets produced the largest absolute error and variability between teams, with the least agreement (ICC and LOA) with ground-truth results. Fifty percent of the submissions were replicated, and one produced three times larger CBF errors (46.59 mL/100 g/min) compared to submitted results. Conclusions: Variability in CBF measurements, influenced by differences in image processing, especially to compensate for motion, highlights the significance of standardizing ASL analysis workflows. We provide a recommendation for ASL processing based on top-performing approaches as a step toward ASL standardization

Reproducibility of arterial spin labeling cerebral blood flow image processing:A report of the ISMRM open science initiative for perfusion imaging (OSIPI) and the ASL MRI challenge

Purpose: Arterial spin labeling (ASL) is a widely used contrast-free MRI method for assessing cerebral blood flow (CBF). Despite the generally adopted ASL acquisition guidelines, there is still wide variability in ASL analysis. We explored this variability through the ISMRM-OSIPI ASL-MRI Challenge, aiming to establish best practices for more reproducible ASL analysis. Methods: Eight teams analyzed the challenge data, which included a high-resolution T1-weighted anatomical image and 10 pseudo-continuous ASL datasets simulated using a digital reference object to generate ground-truth CBF values in normal and pathological states. We compared the accuracy of CBF quantification from each team's analysis to the ground truth across all voxels and within predefined brain regions. Reproducibility of CBF across analysis pipelines was assessed using the intra-class correlation coefficient (ICC), limits of agreement (LOA), and replicability of generating similar CBF estimates from different processing approaches. Results: Absolute errors in CBF estimates compared to ground-truth synthetic data ranged from 18.36 to 48.12 mL/100 g/min. Realistic motion incorporated into three datasets produced the largest absolute error and variability between teams, with the least agreement (ICC and LOA) with ground-truth results. Fifty percent of the submissions were replicated, and one produced three times larger CBF errors (46.59 mL/100 g/min) compared to submitted results. Conclusions: Variability in CBF measurements, influenced by differences in image processing, especially to compensate for motion, highlights the significance of standardizing ASL analysis workflows. We provide a recommendation for ASL processing based on top-performing approaches as a step toward ASL standardization.</p

ISMRM Open Science Initiative for Perfusion Imaging (OSIPI): ASL pipeline inventory

Purpose: To create an inventory of image processing pipelines of arterial spin labeling (ASL) and list their main features, and to evaluate the capability, flexibility, and ease of use of publicly available pipelines to guide novice ASL users in selecting their optimal pipeline. Methods: Developers self‐assessed their pipelines using a questionnaire developed by the Task Force 1.1 of the ISMRM Open Science Initiative for Perfusion Imaging. Additionally, each publicly available pipeline was evaluated by two independent testers with basic ASL experience using a scoring system created for this purpose. Results: The developers of 21 pipelines filled the questionnaire. Most pipelines are free for noncommercial use (n = 18) and work with the standard NIfTI (Neuroimaging Informatics Technology Initiative) data format (n = 15). All pipelines can process standard 3D single postlabeling delay pseudo‐continuous ASL images and primarily differ in their support of advanced sequences and features. The publicly available pipelines (n = 9) were included in the independent testing, all of them being free for noncommercial use. The pipelines, in general, provided a trade‐off between ease of use and flexibility for configuring advanced processing options. Conclusion: Although most ASL pipelines can process the common ASL data types, only some (namely, ASLPrep, ASLtbx, BASIL/Quantiphyse, ExploreASL, and MRICloud) are well‐documented, publicly available, support multiple ASL types, have a user‐friendly interface, and can provide a useful starting point for ASL processing. The choice of an optimal pipeline should be driven by specific data to be processed and user experience, and can be guided by the information provided in this ASL inventory

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

Imaging blood-brain barrier dysfunction: A state-of-the-art review from a clinical perspective

The blood-brain barrier (BBB) consists of specialized cells that tightly regulate the in- and outflow of molecules from the blood to brain parenchyma, protecting the brain’s microenvironment. If one of the BBB components starts to fail, its dysfunction can lead to a cascade of neuroinflammatory events leading to neuronal dysfunction and degeneration. Preliminary imaging findings suggest that BBB dysfunction could serve as an early diagnostic and prognostic biomarker for a number of neurological diseases. This review aims to provide clinicians with an overview of the emerging field of BBB imaging in humans by answering three key questions: (1. Disease) In which diseases could BBB imaging be useful? (2. Device) What are currently available imaging methods for evaluating BBB integrity? And (3. Distribution) what is the potential of BBB imaging in different environments, particularly in resource limited settings? We conclude that further advances are needed, such as the validation, standardization and implementation of readily available, low-cost and non-contrast BBB imaging techniques, for BBB imaging to be a useful clinical biomarker in both resource-limited and well-resourced settings