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Blood-brain barrier (BBB) dysfunction is considered a hallmark of Alzheimer’s disease (AD), making non-invasive imaging of BBB with arterial spin labeling (ASL) MRI a potential imaging biomarker (BBB-ASL). However, the normal BBB development over the lifespan is unknown. Here, we created population-based BBB-ASL permeability reference maps, and aimed to investigate associations between BBB-ASL, chronological age, and biological cerebrovascular age – expressed as white matter hyperintensities (WMH) volume

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 ADrelated 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.

The Brain Imaging Data Structure (BIDS) is a community-driven standard for the organization of data and metadata from a growing range of neuroscience modalities. This paper is meant as a history of how the standard has developed and grown over time. We outline the principles behind the project, and the mechanisms by which it has been extended. We also discuss the lessons learned through the project, with the aim of enabling researchers in other domains to learn from the success of BIDS.

Gadolinium-based contrast agents (GBCA) form the cornerstone of current primary brain tumor MRI protocols at all stages of the patient journey. Though an imperfect of tumor grade, GBCA is repeatedly used for diagnosis and monitoring. In practice, however, radiologists will encounter situations where GBCA injection is unwanted or of doubtful benefit. Reducing GBCA administration could improve the patient burden of (repeated) imaging, especially in vulnerable patient groups such as children, minimize risks of putative side effects, as well as benefit costs, logistics, and the environmental footprint. This review presents standard imaging strategies to reduce GBCA exposure for pediatric and adult patients with primary brain tumors, including the effect of prolonging follow-up intervals and omitting contrast-enhanced sequences. The potential of novel pulse sequences, such as arterial spin labeling, and upcoming artificial intelligence methods, e.g., to generate synthetic post-contrast images, promise to replace GBCA-dependent approaches. To attain a concise summary of the knowledge in the field, gliomas and meningiomas as typical representatives of primary brain tumors are the review’s focus. Special attention is paid to study quality and real-life applicability.

Purpose: Arterial Spin Labeling (ASL) is widely used in clinical research as a contrast-free MRI method for assessment of cerebral blood flow (CBF). While the recommended guideline for ASL acquisition is generally adopted to standardize quantification of CBF, ASL analysis still produces wide variability in CBF estimates, limiting research and clinical interpretation of ASL results. This study explored the extent of variability in ASL CBF quantification through the ISMRM OSIPI ASL MRI Challenge. The goal of the challenge was to minimize sources of variability in ASL analysis by establishing best practice in ASL data processing to make ASL analysis more reproducible and clinically meaningful. Methods: Eight international teams analyzed the challenge data consisting of a high-resolution T1- weighted anatomical image and ten pseudo-continuous ASL (PCASL) datasets. The datasets were simulated using an ASL digital reference object to produce ground-truth CBF values in normal and pathological states. The accuracy of CBF quantification from each team’s analysis was compared to ground-truth values across all voxels and within pre-defined brain regions. Reproducibility of CBF estimates across analysis pipelines was assessed using intra-class correlation coefficient (ICC), the limits of agreement (LOA) and the replicability of generating similar CBF estimates from the image processing approaches as documented. Results: The absolute errors in CBF estimates compared to the ground-truth synthetic data ranged from 18.36 to 48.12 ml/100g/min. Realistic motion incorporated in three of the ten synthetic data produced the largest absolute CBF error, largest variability between teams, and the least agreement (ICC and LOA) with ground truth results. Fifty percent (4/8) of the teams’ methods were replicated, and one method produced three times larger CBF errors (46.59 ml/100g/min) compared to submitted results. Conclusions: The apparent variability in CBF measurements, influenced by diff

BACKGROUND Breast cancer patients may experience cognitive difficulties after chemotherapy. PURPOSE To investigate whether an exercise intervention can affect cerebral blood flow (CBF) in breast cancer patients and if CBF changes relate to memory function. STUDY TYPE Prospective. POPULATION Chemotherapy-treated breast cancer patients with cognitive problems, and with relatively low physical activity levels were randomized to an exercise intervention (n=91) or control group (n=90). FIELDSTRENGTH/SEQUENCE A 3-T arterial spin labeling CBF scan was performed. ASSESSMENT The 6-month intervention consisted of (supervised) aerobic and strength training, 4x1 hour/week. Measurements at baseline (2-4 years post-diagnosis) and after six months included the arterial spin labeling CBF scan, from which we calculated gray matter CBF in the whole brain, hippocampus, anterior cingulate cortex, and posterior cingulate cortex. Furthermore, we measured physical fitness and memory functioning. STATISTICAL TESTS Multiple regression analyses with a two-sided alpha of 0.05 for all analyses. RESULTS We observed significant improvement in physical fitness (VO2peak) in the intervention group (n=53) compared to controls (n=51, B1.47, 95%CI:0.44; 2.50), nevertheless no intervention effects on CBF were found (e.g. whole brain: B0.98, 95%CI:-2.38; 4.34). Highly fatigued patients showed larger, but not significant, treatment effects. Additionally, change in physical fitness, from baseline to post-intervention, was positively associated with changes in CBF (e.g., whole brain: B0.75, 95%CI:0.07; 1.43). However, we observed no relation between CBF changes and change in memory performance. DATA CONCLUSION The exercise intervention did not affect CBF of cognitively affected breast cancer patients. However, a change in physical fitness was related to a change in CBF, but a change in CBF was not associated with memory functioning.

The 2015 consensus statement published by the ISMRM Perfusion Study Group and the EU COST Action ‘ASL in Dementia’ aimed to encourage the implementation of robust Arterial Spin Labeling (ASL) perfusion MRI for clinical applications and promote consistency across scanner types, sites, and studies. Subsequently, the recommended 3D pseudo-continuous ASL sequence has been implemented by most major MRI manufacturers. However, ASL remains a rapidly and widely developing field, leading inevitably to further divergence of the technique and its associated terminology, which could cause confusion and hamper research reproducibility. On behalf of the ISMRM Perfusion Study Group, and as part of the ISMRM Open Science Initiative for Perfusion Imaging (OSIPI), the ASL Lexicon Task-Force has been working on the development of an ‘ASL Lexicon and Reporting Recommendations’ for perfusion imaging and analysis, aiming to 1) develop standardized, consensus nomenclature and terminology for the broad range of ASL imaging techniques and parameters, as well as the physiological constants required for quantitative analysis, and 2) provide a community-endorsed recommendation on the imaging parameters that we encourage authors to include when describing ASL methods in scientific reports/articles. In this manuscript, the sequences and parameters in (pseudo-)continuous ASL, pulsed ASL, velocity-selective ASL and multi-timepoint ASL for brain perfusion imaging are included. However, the content of the lexicon is not intended to be limited to these techniques, and this paper provides the foundation for a growing online inventory that will be extended by the community as further methods and improvements are developed and established.

Purpose: To create an inventory of automated image processing pipelines of Arterial Spin Labeling (ASL) and summarize their features and accessibility for users to choose an optimal pipeline to fit their needs. Methods: Pipeline developers were invited to self-assess their pipelines using a questionnaire developed by the Task Force 1.1 of the Open Science Initiative for Perfusion Imaging (OSIPI). Additionally, publicly available pipelines were evaluated by two independent testers using an objective unified scoring system. The testing focused on the capability, flexibility, and ease of use of the pipelines on various datasets. Results: The developers of twenty-one pipelines filled in the questionnaire. Most pipelines support data from the three major vendors, i.e., GE (n=15), Philips (n=15), and Siemens (n=16), are free for research (n=18), work with the standard neuroimaging data format NIfTI (n=15), and can process standard 3D single PLD pseudo-continuous ASL images (n=21). Pipelines mainly differed in their support of advanced sequences and advanced features. Nine publicly available pipelines were included in the independent testing. Whereas certain pipelines were easy to use for users without programming skills, other pipelines offered more flexibility for configuring advanced processing options. Conclusion: ASL data from the most commonly used ASL sequences saved in the standard neuroimaging data formats can be easily processed using publicly available pipelines. A specific choice of a pipeline should consider specific requirements on features and users’ skills, and the ASL inventory can serve as a valuable guide to facilitate this choice.

Genetic frontotemporal dementia is most commonly attributable to mutations in the C9orf72, GRN, or MAPT genes. The disease has near-complete penetrance, making presymptomatic carriers an ideal population for ascertaining the earliest changes in disease progression and the identification of suitable biomarkers for designing therapeutic trials when minimal neuronal loss has occurred. Cerebral perfusion, as measured by arterial spin labelling (ASL) MRI, has shown promise in being one such biomarker. However, longitudinal profiles of change in perfusion over time in presymptomatic carriers across all three genetic subgroups are lacking. Using data from the multicenter GENetic Frontotemporal dementia Initiative, we investigated longitudinal profiles of cerebral perfusion using ASL-MRI in C9orf72 (n = 42), GRN (n = 70), and MAPT (n = 31) presymptomatic mutation carriers and non-carrier controls (n = 158). ASL and T1w scans were processed with the ExploreASL pipeline to produce partial volume corrected perfusion images, which were parcellated to extract mean perfusion values from whole brain grey matter and regions defined by the second version of the automated anatomical atlas (AAL2). Linear mixed effects models were used to assess longitudinal perfusion change. Mutation carrier groups and non-carriers were statistically indistinguishable by baseline demographic and clinical measures. Decline in whole brain grey matter perfusion over time was more pronounced in all three carrier subgroups relative to controls, with changes most pronounced in GRN, followed by C9orf72 and MAPT variants. Additionally, GRN and MAPT groups featured global grey matter hypoperfusion relative to non-carrier controls as early as one year after baseline measurement, with C9orf72 featuring significant hypoperfusion after two years. Region of interest analysis demonstrated that each genetic subgroup had its own regional profile in terms of longitudinal perfusion decline. Perfusion decline in C9orf72

Todate,multipleadvancedmagneticresonanceimaging(MRI)methodsbeyondconventionalqualitativestructuralimagingforthediagnosis,prognosis,andtreatmentfollow-upofgliomahavedemonstratedtheirutilityforclinicalstudies.However,thesemethodsoftenrelyoncomplexoff-scannerprocessingtoyieldthemostinformationandtoextractquantitativebiomarkers,limitingtheirpracticaluseforstudies,aswellastheirclinicaltranslation.Whilecommunity-drivensoftwaresolutionsexistfortheseadvancedMRImethods,manyaspiringclinicalresearchersfacechallengesinacquiringthenecessaryknowledgetoeffectivelyapplythesetools.Thisguide,aninitiativeoftheGliomaMRimaging2.0network(GliMR),aimstoprovideanoverviewofexistingsolutions,communities,andrepositorieswiththeultimategoalofenablingstandardization,openscience,andreproduciblequantitativeimagingstudiesofgliomas.Yet,mostofthereviewedtoolsandapproachestoimagedataanalysesmayalsobeusedinthecontextofstudiesondiseasesotherthanglioma.

Background: Decreased cerebral blood flow (CBF) and deterioration of blood-brain barrier (BBB) are suggested to be precursor conditions of cognitive impairment. Using a novel multi-echo-time arterial spin labelling (ASL) protocol, we examined the time of exchange (Tex) of water across the BBB as a measurement of BBB permeability. We further examined the association of cardiovascular risk factors with Tex in an ongoing cohort study. Method: Data (n=29, mean age: 55.9±6.1years, 69% women) were drawn from Neurological biomarkers of Blood, MRI and Cognition (NEURO-BMC) study performed at National University of Singapore. NEURO-BMC is an ongoing prospective cohort study (age: 45-65 years) on brain changes in a subclinical phase of cognitive impairment. A multi-echo, Hadamard-encoded multi-post-labelling-delay pseudo-continuous ASL (PCASL) protocol was used on a 3T scanner. ExploreASL was used with a modified version of FSL FABBER(4) to quantify cerebral blood flow (CBF), arterial transit time (ATT), and Tex. ASL-extracted parameters were compared with cardiovascular risk parameters such as blood pressure (BP), BMI and smoking status. Result: High systolic and diastolic BP were associated with significantly reduced Tex (Fig 1). Additionally, higher systolic and diastolic BP showed a trend of increased ATT and reduced CBF, though the associations were not statistically significant (Table 1). High BMI had a significant association with increased ATT and reduced CBF. However, no trend was observed between BMI and Tex. Participants who ever smoked were observed to have a reduced Tex and CBF and increased ATT, but statistical significance was only found for CBF (Fig 1). Conclusion: In this pilot study, we showed that BBB-ASL-derived parameters - ATT, CBF, and Tex - were associated with BP, BMI, and smoking status. While the sample size for this preliminary analysis was too small to make a definitive conclusion as not all associations were statistically significant, all studied

Background: Decreased cerebral blood flow (CBF) and deterioration of blood-brain barrier (BBB) are suggested to be precursor conditions of cognitive impairment. Using a novel multi-echo-time arterial spin labelling (ASL) protocol, we examined the time of exchange (Tex) of water across the BBB as a measurement of BBB permeability. We further examined the association of cardiovascular risk factors with Tex in an ongoing cohort study. Method: Data (n=29, mean age: 55.9±6.1years, 69% women) were drawn from Neurological biomarkers of Blood, MRI and Cognition (NEURO-BMC) study performed at National University of Singapore. NEURO-BMC is an ongoing prospective cohort study (age: 45-65 years) on brain changes in a subclinical phase of cognitive impairment. A multi-echo, Hadamard-encoded multi-post-labelling-delay pseudo-continuous ASL (PCASL) protocol was used on a 3T scanner. ExploreASL was used with a modified version of FSL FABBER(4) to quantify cerebral blood flow (CBF), arterial transit time (ATT), and Tex. ASL-extracted parameters were compared with cardiovascular risk parameters such as blood pressure (BP), BMI and smoking status. Result: High systolic and diastolic BP were associated with significantly reduced Tex (Fig 1). Additionally, higher systolic and diastolic BP showed a trend of increased ATT and reduced CBF, though the associations were not statistically significant (Table 1). High BMI had a significant association with increased ATT and reduced CBF. However, no trend was observed between BMI and Tex. Participants who ever smoked were observed to have a reduced Tex and CBF and increased ATT, but statistical significance was only found for CBF (Fig 1). Conclusion: In this pilot study, we showed that BBB-ASL-derived parameters - ATT, CBF, and Tex - were associated with BP, BMI, and smoking status. While the sample size for this preliminary analysis was too small to make a definitive conclusion as not all associations were statistically significant, all studied

Background: Decreased cerebral blood flow (CBF) and deterioration of blood-brain barrier (BBB) are suggested to be precursor conditions of cognitive impairment. Using a novel multi-echo-time arterial spin labelling (ASL) protocol, we examined the time of exchange (Tex) of water across the BBB as a measurement of BBB permeability. We further examined the association of cardiovascular risk factors with Tex in an ongoing cohort study. Method: Data (n=29, mean age: 55.9±6.1years, 69% women) were drawn from Neurological biomarkers of Blood, MRI and Cognition (NEURO-BMC) study performed at National University of Singapore. NEURO-BMC is an ongoing prospective cohort study (age: 45-65 years) on brain changes in a subclinical phase of cognitive impairment. A multi-echo, Hadamard-encoded multi-post-labelling-delay pseudo-continuous ASL (PCASL) protocol was used on a 3T scanner. ExploreASL was used with a modified version of FSL FABBER(4) to quantify cerebral blood flow (CBF), arterial transit time (ATT), and Tex. ASL-extracted parameters were compared with cardiovascular risk parameters such as blood pressure (BP), BMI and smoking status. Result: High systolic and diastolic BP were associated with significantly reduced Tex (Fig 1). Additionally, higher systolic and diastolic BP showed a trend of increased ATT and reduced CBF, though the associations were not statistically significant (Table 1). High BMI had a significant association with increased ATT and reduced CBF. However, no trend was observed between BMI and Tex. Participants who ever smoked were observed to have a reduced Tex and CBF and increased ATT, but statistical significance was only found for CBF (Fig 1). Conclusion: In this pilot study, we showed that BBB-ASL-derived parameters - ATT, CBF, and Tex - were associated with BP, BMI, and smoking status. While the sample size for this preliminary analysis was too small to make a definitive conclusion as not all associations were statistically significant, all studied

Blood-brain barrier (BBB) dysfunction is considered a hallmark of Alzheimer’s disease (AD), making non-invasive imaging of BBB with arterial spin labeling (ASL) MRI a potential imaging biomarker (BBB-ASL). However, the normal BBB development over the lifespan is unknown. Here, we created population-based BBB-ASL permeability reference maps, and aimed to investigate associations between BBB-ASL, chronological age, and biological cerebrovascular age – expressed as white matter hyperintensities (WMH) volume

Cardiovascular and cerebrovascular pathology may accelerate brain aging and cognitive decline. Structural cerebrovascular imaging biomarkers, such as white matter hyperintensities, reflect mostly irreversible accumulated damage. In contrast, cerebral blood flow (CBF), measured with arterial spin labelling (ASL) perfusion MRI, is a potential early haemodynamic biomarker of cognitive impairment. However, our understanding of physiological CBF variability and its relation with cognition is limited.

Blood-brain barrier (BBB) dysfunction is considered a hallmark of Alzheimer’s disease (AD), making non-invasive imaging of BBB with arterial spin labeling (ASL) MRI a potential imaging biomarker (BBB-ASL). However, the normal BBB development over the lifespan is unknown. Here, we created population-based BBB-ASL permeability reference maps, and aimed to investigate associations between BBB-ASL, chronological age, and biological cerebrovascular age – expressed as white matter hyperintensities (WMH) volume

Subtle changes in BBB integrity might be missed by contrast-enhanced T1-weighted MRI. Blood-brain barrier arterial spin labeling (BBB-ASL) is a new technique to assess BBB disruptions. In this work, we measured the cerebral blood flow (CBF) and exchange time (Tex) values of the tumor, normal-appearing white matter, and normal-appearing gray matter regions in gliomas using BBB-ASL technique. Our results indicated higher CBF and leakier BBB in contrast-enhanced regions of gliomas than in the normal-appearing GM.

Arterial transit artifacts (ATAs) in arterial spin labeling (ASL) images are common in populations with prolonged arterial transit time (ATT) and may be associated with vascular insufficiency. The spatial coefficient of variance (sCoV) of ASL images can quantify the presence of these artifacts. Vascular insufficiency could contribute to the development of white matter hyperintensities (WMH), a common marker of cerebral small vessel disease. We demonstrated that baseline sCoV of CBF is associated with WMH at baseline and predicts WMH volume change, in a cognitively unimpaired population of 88 subjects.

Arterial transit artifacts (ATAs) in arterial spin labeling (ASL) images are common in populations with prolonged arterial transit time (ATT) and may be associated with vascular insufficiency. The spatial coefficient of variance (sCoV) of ASL images can quantify the presence of these artifacts. Vascular insufficiency could contribute to the development of white matter hyperintensities (WMH), a common marker of cerebral small vessel disease. We demonstrated that baseline sCoV of CBF is associated with WMH at baseline and predicts WMH volume change, in a cognitively unimpaired population of 88 subjects.

Blood-brain barrier (BBB) dysfunction is considered a hallmark of Alzheimer’s disease (AD), making non-invasive imaging of BBB with arterial spin labeling (ASL) MRI a potential imaging biomarker (BBB-ASL). However, the normal BBB development over the lifespan is unknown. Here, we created population-based BBB-ASL permeability reference maps, and aimed to investigate associations between BBB-ASL, chronological age, and biological cerebrovascular age – expressed as white matter hyperintensities (WMH) volume

Decreased cerebral blood flow (CBF) and deterioration of blood-brain barrier (BBB) are suggested to be precursor conditions of cognitive impairment. Using a novel multi-echo-time arterial spin labelling (ASL) protocol, we examined the time of exchange (Tex) of water across the BBB as a measurement of BBB permeability. We further examined the association of cardiovascular risk factors with Tex in an ongoing cohort study.

Blood-brain-barrier (BBB) dysfunction is a hallmark of aging-related disorders, including cerebral small vessel disease and Alzheimer’s disease. An emerging biomarker of BBB dysfunction is time of exchange (Tex) of water across the BBB as measured by multi-echo arterial spin labeling MRI. We evaluated Tex across the age spectrum in 40 adults from two cohorts of healthy controls, and demonstrated that Tex is higher in gray than in white matter, higher in females than in males, and that Tex decreases with age. These findings suggest that BBB permeability changes over the lifespan can be investigated using arterial spin labeling approaches.

One of the earliest signs of Alzheimer’s disease (AD) is the loss of blood-brain barrier (BBB) integrity. Arterial spin labeling (ASL) MRI is a non-invasive way to measure perfusion and several other hemodynamic and physiological parameters, including vascular permeability. The DEveloping BBB-ASL as non-Invasive Early biomarker (DEBBIE) consortium aims to develop and integrate innovative techniques to allow robust BBB permeability assessments by ASL to develop a sensitive, non-invasive, and early biomarker for AD and related dementias. This work summarizes our planned efforts to develop and establish an MRI-based BBB permeability biomarker.

While mid-life cardiovascular pathology may lead to late-life cognitive decline, our understanding of the role of cerebrovascular health as an intermediate biomarker is limited. We explored the association between cardiovascular health biomarkers and cross-sectional and longitudinal cerebrovascular health assessed by ASL MRI in Insight46, a well-characterised cognitively normal population-based sample. We found several cross-sectional and longitudinal associations between blood pressure and CBF. These findings suggest that the effects of BP on cerebrovascular health can be imaged with ASL perfusion MRI, possibly offering opportunities to prevent or intervene before cognitive decline sets in.

IDH genotype status is an important marker in glioma diagnostics. Given that IDH mutation affects the tumor vascularization pattern, perfusion imaging has the potential to become a non-invasive tumor histopathology assessor. In this study, two methods of perfusion MRI – Dynamic Susceptibility Contrast (DSC) and Arterial Spin Labeling (ASL) – were compared in their ability to assess IDH mutation status. DSC- and ASL-derived perfusion maps correlated significantly and were feasible parameters in the IDH classification task. Mean tumor CBF quantified with ASL had the highest AUC score, sensitivity, and specificity, supporting the feasibility of using ASL in clinical glioma diagnostics.

While mid-life cardiovascular pathology may lead to late-life cognitive decline, our understanding of the role of cerebrovascular health as an intermediate biomarker is limited. We explored the association between cardiovascular health biomarkers and cross-sectional and longitudinal cerebrovascular health assessed by ASL MRI in Insight46, a well-characterised cognitively normal population-based sample. We found several cross-sectional and longitudinal associations between blood pressure and CBF. These findings suggest that the effects of BP on cerebrovascular health can be imaged with ASL perfusion MRI, possibly offering opportunities to prevent or intervene before cognitive decline sets in.

Blood-brain-barrier (BBB) dysfunction is a hallmark of aging-related disorders, including cerebral small vessel disease and Alzheimer’s disease. An emerging biomarker of BBB dysfunction is time of exchange (Tex) of water across the BBB as measured by multi-echo arterial spin labeling MRI. We evaluated Tex across the age spectrum in 40 adults from two cohorts of healthy controls, and demonstrated that Tex is higher in gray than in white matter, higher in females than in males, and that Tex decreases with age. These findings suggest that BBB permeability changes over the lifespan can be investigated using arterial spin labeling approaches.

Introduction: Loss of blood-brain barrier (BBB) integrity is hypothesized to be one of the earliest microvascular signs of Alzheimer’s disease (AD). Arterial spin labeling (ASL) perfusion MRI has recently been adapted to map the BBB permeability non-invasively. This article outlines the study design of the DEveloping BBB-ASL as a non-Invasive Early biomarker (DEBBIE) consortium, focused on investigating the potential of BBB-ASL as an early biomarker for AD (DEBBIE-AD). Methods: DEBBIE-AD consists of 13 cohorts enrolling participants from subjective cognitive decline to AD, as well as healthy controls across the lifespan. The reproducibility and accuracy of BBB-ASL will be evaluated in healthy participants, and its clinical value will be evaluated with both established and novel AD biomarkers. Expected endpoints: DEBBIE-AD aims to provide evidence on the ability of BBB-ASL to measure BBB permeability and demonstrate its utility in AD-related pathologies, which may provide new targets for treatment.

While mid-life cardiovascular pathology may lead to late-life cognitive decline, our understanding of the role of cerebrovascular health as an intermediate biomarker is limited. We explored the association between cardiovascular health biomarkers and cross-sectional and longitudinal cerebrovascular health assessed by ASL MRI in Insight46, a well-characterised cognitively normal population-based sample. We found several cross-sectional and longitudinal associations between blood pressure and CBF. These findings suggest that the effects of BP on cerebrovascular health can be imaged with ASL perfusion MRI, possibly offering opportunities to prevent or intervene before cognitive decline sets in.

VASARI feature are a controlled vocabulary aiming to create reproducible terminology for glioma interpretation

Decreased cerebral blood flow (CBF) and deterioration of blood-brain barrier (BBB) are suggested to be precursor conditions of cognitive impairment. Using a novel multi-echo-time arterial spin labelling (ASL) protocol, we examined the time of exchange (Tex) of water across the BBB as a measurement of BBB permeability. We further examined the association of cardiovascular risk factors with Tex in an ongoing cohort study.

IDH genotype status is an important marker in glioma diagnostics. Given that IDH mutation affects the tumor vascularization pattern, perfusion imaging has the potential to become a non-invasive tumor histopathology assessor. In this study, two methods of perfusion MRI – Dynamic Susceptibility Contrast (DSC) and Arterial Spin Labeling (ASL) – were compared in their ability to assess IDH mutation status. DSC- and ASL-derived perfusion maps correlated significantly and were feasible parameters in the IDH classification task. Mean tumor CBF quantified with ASL had the highest AUC score, sensitivity, and specificity, supporting the feasibility of using ASL in clinical glioma diagnostics.

One of the earliest signs of Alzheimer’s disease (AD) is the loss of blood-brain barrier (BBB) integrity. Arterial spin labeling (ASL) MRI is a non-invasive way to measure perfusion and several other hemodynamic and physiological parameters, including vascular permeability. The DEveloping BBB-ASL as non-Invasive Early biomarker (DEBBIE) consortium aims to develop and integrate innovative techniques to allow robust BBB permeability assessments by ASL to develop a sensitive, non-invasive, and early biomarker for AD and related dementias. This work summarizes our planned efforts to develop and establish an MRI-based BBB permeability biomarker.

Cardiovascular and cerebrovascular pathology may accelerate brain aging and cognitive decline. Structural cerebrovascular imaging biomarkers, such as white matter hyperintensities, reflect mostly irreversible accumulated damage. In contrast, cerebral blood flow (CBF), measured with arterial spin labelling (ASL) perfusion MRI, is a potential early haemodynamic biomarker of cognitive impairment. However, our understanding of physiological CBF variability and its relation with cognition is limited.

While mid-life cardiovascular pathology may lead to late-life cognitive decline, our understanding of the role of cerebrovascular health as an intermediate biomarker is limited. We explored the association between cardiovascular health biomarkers and cross-sectional and longitudinal cerebrovascular health assessed by ASL MRI in Insight46, a well-characterised cognitively normal population-based sample. We found several cross-sectional and longitudinal associations between blood pressure and CBF. These findings suggest that the effects of BP on cerebrovascular health can be imaged with ASL perfusion MRI, possibly offering opportunities to prevent or intervene before cognitive decline sets in.

Subtle changes in BBB integrity might be missed by contrast-enhanced T1-weighted MRI. Blood-brain barrier arterial spin labeling (BBB-ASL) is a new technique to assess BBB disruptions. In this work, we measured the cerebral blood flow (CBF) and exchange time (Tex) values of the tumor, normal-appearing white matter, and normal-appearing gray matter regions in gliomas using BBB-ASL technique. Our results indicated higher CBF and leakier BBB in contrast-enhanced regions of gliomas than in the normal-appearing GM.

This review article focuses on clinical applications of arterial spin labeling (ASL) and is part of a wider effort from the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group to update and expand on the recommendations provided in the 2015 the consensus paper on ASL. While the 2015 consensus paper provided general guidelines for clinical applications of ASL MRI, there was a lack of guidance on disease-specific parameters. Since that time, the clinical availability and o clinical demand for ASL MRI has increased. This position paper provides guidance on using ASL in specific clinical scenarios, including acute ischemic stroke and steno-occlusive disease, arteriovenous malformations and fistulas, tumors, neurodegenerative disease, pediatric applications, and seizures/epilepsy, focusing on disease-specific considerations for sequence optimization and interpretation. We present several neuroradiological applications where ASL can provide unique diagnostic information. This guidance is intended for anyone interested in using ASL in a routine clinical setting — i.e., on a single-subject basis rather than in cohort studies — building on the previous ASL consensus review.

Preoperative clinical MRI protocols for gliomas, brain tumors with dismal outcomes due to their infiltrative properties, still rely on conventional structural MRI, which does not deliver information on tumor genotype and is limited in the delineation of diffuse gliomas. The GliMR COST action wants to raise awareness about the state of the art of advanced MRI techniques in gliomas and their possible clinical translation. This review describes current methods, limits, and applications of advanced MRI for the preoperative assessment of glioma, summarizing the level of clinical validation of different techniques. In this second part, we review magnetic resonance spectroscopy (MRS), chemical exchange saturation transfer (CEST), susceptibility-weighted imaging (SWI), MRI-PET, MR elastography (MRE), and MR-based radiomics applications. The first part of this review addresses dynamic susceptibility contrast (DSC) and dynamic contrast-enhanced (DCE) MRI, arterial spin labeling (ASL), diffusion-weighted MRI, vessel imaging, and magnetic resonance fingerprinting (MRF).

Background: The blood-brain barrier (BBB) consists of specialized cells that tightly regulate the in- and outflow of molecules from the blood to the 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. Main body: 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 across all settings, particularly in resource-limited settings? Conclusion: BBB imaging holds the potential to enable earlier diagnosis and aid in the recruitment of individuals and rapid assessment of treatment response in clinical trials. 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.

To date, perfusion simulations in the human brain have been limited to a relatively small number of patient-specific cases. Here, a pipeline relying on magnetic resonance imaging (MRI) is proposed to overcome this limitation. The computational geometry is adjusted using T1-weighted MRI, whereas the perfusion model parameters are tuned based on arterial spin labeling perfusion MRI. A cohort of 75 patients is considered to demonstrate that the pipeline is suitable to generate virtual patients with statistically realistic cerebral blood flow maps. In the future, in silico clinical trials will be conducted using similar virtual cohorts to improve ischaemic stroke interventions.

Preoperative clinical MRI protocols for gliomas, brain tumors with dismal outcomes due to their infiltrative properties, still rely on conventional structural MRI, which does not deliver information on tumor genotype and is limited in the delineation of diffuse gliomas. The GliMR COST action wants to raise awareness about the state of the art of advanced MRI techniques in gliomas and their possible clinical translation or lack thereof. This review describes current methods, limits, and applications of advanced MRI for the preoperative assessment of glioma, summarizing the level of clinical validation of different techniques. In this first part, we discuss dynamic susceptibility contrast (DSC) and dynamic contrast-enhanced (DCE) MRI, arterial spin labeling (ASL), diffusion-weighted MRI, vessel imaging, and magnetic resonance fingerprinting (MRF). The second part of this review addresses magnetic resonance spectroscopy (MRS), chemical exchange saturation transfer (CEST), susceptibility-weighted imaging (SWI), MRI-PET, MR elastography (MRE), and MR-based radiomics applications.

BACKGROUND Amide proton transfer (APT) imaging is a chemical exchange saturation transfer (CEST) technique offering potential clinical applications in patients with brain tumors. PURPOSE To investigate whether cerebral APT-CEST is sufficiently reproducible in healthy tissue and glioma for clinical use at 3T. STUDY TYPE Prospective, longitudinal SUBJECTS Twenty-one healthy volunteers (M:F = 10:11; age 39±11 years) and six glioma patients (M:F = 3:3; age 50±17 years: four glioblastomas, one oligodendroglioma, one suspected low-grade glioma). FIELD STRENGTH/SEQUENCE 3T, SPACE-CEST ASSESSMENT APT-CEST measurement reproducibility was assessed within-session (glioma patients, healthy volunteers), and between-sessions and between-days (healthy volunteers). The standard deviation of the within-subject difference (SDdiff) was calculated in tumor regions of interest (ROI), and eight ROIs at relevant locations including a whole-brain ROI. STATISTICAL TESTS Brown-Forsythe tests and variance component analyses (VCA) were used to assess the reproducibility of ROIs for the three reproducibility time intervals. Intraclass correlation coefficient (ICC) was used to assess agreement between the ROIs for the three reproducibility time intervals. RESULTS APT-CEST magnetization transfer ratio asymmetry (MTRasym) was 0.89±0.96% on average in healthy brain tissue and 1.59±0.67% in tumor tissue. Intratumoral mean MTRasym was significantly higher than MTRasym in healthy-appearing tissue in patients (0.5±0.46%; P< 0.001). The APTCEST difference between GBMs and contralateral tissue was 1.11%. The average within-session, between-sessions, and between-days SDdiff of healthy control brains was 0.2%. The within-session SDdiff of whole-brain was 0.2% in both healthy volunteers and patients, and 0.21% in the segmented tumor. The orbitofrontal gyri were the ROI with the highest within-session SDdiff (0.61%). Within-session reproducibility of ROIs did not differ significantly from between-sessions or

Background: Biological brain age estimates from structural MRI data and their difference from chronological age — the brain age gap (BAG) — have been successfully applied in a range of diseases, but remain limited to capturing structural characteristics only. To incorporate physiological properties, we operationalized ‘Cerebrovascular brain age’ using a combination of structural, and arterial spin labelling (ASL) image data, investigate their optimal feature and algorithm combinations, and evaluate its repeatability. Methods: Healthy participants (n = 341, 62 % female, age 59.7 ± 14.8 years, range: 21 - 95 years) were scanned at baseline and after 1.7 ± 0.5 years (n = 248, 62.9 % female, mean age 62.4 ± 13.3 years, range: 27 - 86). At 3 T MRI, 3D structural T1-weighted (T1w) and Fluid Attenuated Inversion Recovery (FLAIR), and 3D ASL image data were acquired to extract within grey matter (GM) and deep white matter (WM) ROIs: volumetrics, WM hyperintensity volume and count; and cerebral blood flow (CBF) and spatial coefficient of variation (CoV). Multiple combinations of features and machine learning algorithms were evaluated to train brain age algorithms on 70 % of the subjects and evaluated on the remainder, for 300 Monte-Carlo cross-validations, using the Mean Absolute Error (MAE). Feature importance of the best performing model was assessed by determining the feature weights. Model repeatability of the best model was assessed by comparing the BAGs between baseline and follow-up, also using T1w + FLAIR or ASL-only features. Results: The lowest MAE was observed for the ElasticNetCV algorithm using T1w + FLAIR + ASL (MAE = 5.03 ± 0.34 years) and significantly better compared to using T1w + FLAIR (MAE = 6.01 ± 0.39, p < 0.01) and ASL-only features (MAE = 6.04 ± 0.39, R2 = 0.70 ± 0.04, p < 0.01). The three most important features were GM CBF (6.2 ± 1.18), GM/ICV (5.34 ± 0.6), and WM CBF (4.16 ± 0.36). Average baseline and follow-up BAGs were not different (-1.51 ± 6.2

Background: Decreased cerebral blood flow (CBF) and deterioration of blood-brain barrier (BBB) are suggested to be precursor conditions of cognitive impairment. Using a novel multi-echo-time arterial spin labelling (ASL) protocol, we examined the time of exchange (Tex) of water across the BBB as a measurement of BBB permeability. We further examined the association of cardiovascular risk factors with Tex in an ongoing cohort study. Method: Data (n=29, mean age: 55.9±6.1years, 69% women) were drawn from Neurological biomarkers of Blood, MRI and Cognition (NEURO-BMC) study performed at National University of Singapore. NEURO-BMC is an ongoing prospective cohort study (age: 45-65 years) on brain changes in a subclinical phase of cognitive impairment. A multi-echo, Hadamard-encoded multi-post-labelling-delay pseudo-continuous ASL (PCASL) protocol was used on a 3T scanner. ExploreASL was used with a modified version of FSL FABBER(4) to quantify cerebral blood flow (CBF), arterial transit time (ATT), and Tex. ASL-extracted parameters were compared with cardiovascular risk parameters such as blood pressure (BP), BMI and smoking status. Result: High systolic and diastolic BP were associated with significantly reduced Tex (Fig 1). Additionally, higher systolic and diastolic BP showed a trend of increased ATT and reduced CBF, though the associations were not statistically significant (Table 1). High BMI had a significant association with increased ATT and reduced CBF. However, no trend was observed between BMI and Tex. Participants who ever smoked were observed to have a reduced Tex and CBF and increased ATT, but statistical significance was only found for CBF (Fig 1). Conclusion: In this pilot study, we showed that BBB-ASL-derived parameters - ATT, CBF, and Tex - were associated with BP, BMI, and smoking status. While the sample size for this preliminary analysis was too small to make a definitive conclusion as not all associations were statistically significant, all studied

ASL was invented pre-clinically in 19901. The first human applications appeared in 1996 when the post-labeling delay (PLD) was introduced to compensate for the larger distance between labeling in the neck and readout in the brain2. The initially low clinical reliability improved with the implementation of background suppression in 19993,4, the increasing availability of 3T MRI, and the invention of pseudo-continuous ASL in 20085. In 2012, the European COST-action BM1103 "ASL In Dementia” was founded and worked towards reducing the ASL differences between MRI scanners to improve between-center reproducibility. Together with other ISMRM ASL investigators, this resulted in the 2014 consensus paper that recommended single-PLD PCASL with a 3D readout, background suppression, no vascular crushing, the acquisition of a separate M0 image, and a simplified single-compartment quantification model for clinical ASL6.

Practical 30min guide into ASL basics and its use in clinics and clinical research with focus given on the most important guidelines for practical use.

Neurological manifestations are well-recognized in patients with COVID-19, with inflammation and damage to the brain vasculature being the common neuroimaging findings (1). A considerable number of individuals continue to experience – or even develop secondarily – neurological symptoms such as cognitive impairment (2.2% of individuals after SARS-CoV-2 infection) and fatigue or mood swings (3.2%) lasting up to several months after the recovery from COVID-19 (2). This condition is commonly referred to as “long COVID” or “post-COVID condition,” and it creates a substantial burden for social networks, health care, and economics beyond the personal suffering of the patient (3). Understanding the pathophysiological mechanisms of the condition plays a pivotal role in the quest for treatment approaches. Neuroimaging is a key diagnostic technique in this process. An interesting neuroimaging method potentially sensitive to the long-term effects of COVID-19 is MRI perfusion measurement with arterial spin labeling (ASL). Previously, ASL was employed in applications assessing cognitive decline related to microvascular damage and neuroinflammation in the context of cancer therapy or dementia. In these cases, ASL was able to document longitudinal perfusion decrease following radiochemotherapy (4) or to help to detect changes in severe Alzheimer’s disease and even in the prodromal stage (5). The use of ASL perfusion MRI to measure acute and chronic effects of COVID-19 remains limited. ASL was used to demonstrate that a post-COVID olfactory dysfunction was associated with lower tissue perfusion in the orbital and medial frontal regions (6). ASL also showed decreased perfusion in hospitalized subjects with the severe disease three months after discharge (7). However, perfusion still needs to be systematically studied in the largest group of individuals that underwent COVID-19 but did not require hospitalization. In this issue of JMRI, an article by [AuthorName] et al. provides new re

Dear Editor, We have read the letter to the editor from Long et al. with great interest. 1 The authors of this letter stated two methodological concerns on which we will respond. The first concern is that objective criteria are missing for true trigonocephaly or benign metopic ridge. We only included moderate to severe trigonocephaly patients according to the definitions of Birgfeld et al2. Birgfeld et al. provide both a phenotypical distinction between benign metopic ridge and metopic synostosis in their article, as well as illustrative photographs with corresponding CT-imaging in Figure 1.2 Cho et al. and Anolik et al. described CT measures to assess severity of metopic synostosis. In both articles the cut-off point to determine surgical indication remains subjective and poor consensus for the intermediate presentation of metopic craniosynostosis is found.3, 4 In addition, Sisti et al. recently reviewed all literature in Pubmed on trigonocephaly, relating to 15 anthropometric cranial measurements for surgical indications.5 This study illustrates that most papers have a lack of diagnostic criteria for trigonocephaly.5 At our center, the decision for surgery is made through shared decision making with parents. In 2021 this resulted in surgery for 14 patients (moderate or severe presentation) and a conservative treatment for 40 patients (18 mild, and 22 moderate or severe presentation). The second raised concern is the potential blunting effect of sevoflurane on CBF. If it does, a similar effect on both the patients and controls is expected. In our previous ASL study in patients with syndromic craniosynostosis using the same sedation protocol, we found a difference between the groups.6 This suggests that the normal findings in patients with trigonocephaly reflect normal CBF. Very few studies have investigated the influence of anesthesia on ASL CBF in the pediatric population. Carsin-Vu et al. included 84 subjects from 6 months to 15 years and showed no significant CB

Background:Internal carotid-artery stenosis (ICAS)accounts for approximately 10–20% of all strokes.1While effective endovascular treatment is available bycarotid artery stenting (CAS) or carotid endarterectomy(CEA), they come with substantial risks.2Those compet-ing risks complicate treatment decisions especially inasymptomatic ICAS and create the need for improvedpostoperative outcome evaluations. Moreover, revascular-ization effects on cognitive impairments are widelyunknown.3Aim:This MRI-study evaluated endovascular treatmentefficacy in asymptomatic ICAS by clinically applicablehemodynamic imaging. We evaluated capillarytransit-time heterogeneity (CTH) and relative cerebralblood volume (rCBV) with additional visual attentiontesting.Method:16 asymptomatic unilateral high-grade ICAS-patients (age 71.4>5.8y) and 17 age-matched healthycontrols (HC,age 70.8>5.3y) underwent MRI on a 3TPhilips Ingenia twice (10.5 months mean follow-up time).White matter lesions (WML) were derived from FLAIR,4CTH and rCBV from dynamic susceptibility contrast5andtheir lateralization compared within grey matter of themiddle cerebral arterial circulation.6Cognitive testingwith inter-hemispheric sensitivity was based on thetheory of visual attention.7Results/Conclusions:Ipsilateral increases of CTH byþ21.4% (p<0.01, Figure 1(a)) and rCBV byþ4.3%(p<0.03, Figure 1(a)) indicate microvascular impair-ments5 and chronic vasodilation8in ICAS at baseline.After endovascular treatment, hemodynamics recoveredby reduced lateralization of 80% (p<0.04, Figure 1(a)) inline with known short-term effects.9,10However, visualattention deficits persisted (Figure 1(b)).10Here, improvedCTH11might counteract with cognitive decline by microemboli,12as postoperative WML increased slightly butnon-significantly (Figure 1(c)). In conclusion, hemodynam-ics recovered after asymptomatic ICAS revascularization,whereas cognitive impairments seem irreversible

Image-derived phenotypes (IDPs) from multimodal MRI sequences constitute an important resource that allows the characterization of brain alterations in the early stages of Alzheimer diseases and other neurodegenerative conditions. Here, we showed the computation of multimodal IDPs from the European Prevention of Alzheimer Dementia (EPAD) cohort and assessed their relationship with non-imaging markers of neurodegeneration. We demonstrated the clinical relevance of IDPs to uncover early brain alteration in AD by showing expected association with non-imaging data.