Recommendations for quantitative cerebral perfusion MRI using multi-timepoint arterial spin labeling: Acquisition, quantification, and clinical applications.

Accurate assessment of cerebral perfusion is vital for understanding the hemodynamic processes involved in various neurological disorders and guiding clinical decision-making. This guidelines article provides a comprehensive overview of quantitative perfusion imaging of the brain using multi-timepoint arterial spin labeling (ASL), along with recommendations for its acquisition and quantification. A major benefit of acquiring ASL data with multiple label durations and/or post-labeling delays (PLDs) is being able to account for the effect of variable arterial transit time (ATT) on quantitative perfusion values and additionally visualize the spatial pattern of ATT itself, providing valuable clinical insights. Although multi-timepoint data can be acquired in the same scan time as single-PLD data with comparable perfusion measurement precision, its acquisition and postprocessing presents challenges beyond single-PLD ASL, impeding widespread adoption. Building upon the 2015 ASL consensus article, this work highlights the protocol distinctions specific to multi-timepoint ASL and provides robust recommendations for acquiring high-quality data. Additionally, we propose an extended quantification model based on the 2015 consensus model and discuss relevant postprocessing options to enhance the analysis of multi-timepoint ASL data. Furthermore, we review the potential clinical applications where multi-timepoint ASL is expected to offer significant benefits. This article is part of a series published by the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group, aiming to guide and inspire the advancement and utilization of ASL beyond the scope of the 2015 consensus article.

Treatment Response Prediction in Major Depressive Disorder Using Multimodal MRI and Clinical Data: Secondary Analysis of a Randomized Clinical Trial.

OBJECTIVE: Response to antidepressant treatment in major depressive disorder varies substantially between individuals, which lengthens the process of finding effective treatment. The authors sought to determine whether a multimodal machine learning approach could predict early sertraline response in patients with major depressive disorder. They assessed the predictive contribution of MR neuroimaging and clinical assessments at baseline and after 1 week of treatment. METHODS: This was a preregistered secondary analysis of data from the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study, a multisite double-blind, placebo-controlled randomized clinical trial that included 296 adult outpatients with unmedicated recurrent or chronic major depressive disorder. MR neuroimaging and clinical data were collected before and after 1 week of treatment. Performance in predicting response and remission, collected after 8 weeks, was quantified using balanced accuracy (bAcc) and area under the receiver operating characteristic curve (AUROC) scores. RESULTS: A total of 229 patients were included in the analyses (mean age, 38 years [SD=13]; 66% female). Internal cross-validation performance in predicting response to sertraline (bAcc=68% [SD=10], AUROC=0.73 [SD=0.03]) was significantly better than chance. External cross-validation on data from placebo nonresponders (bAcc=62%, AUROC=0.66) and placebo nonresponders who were switched to sertraline (bAcc=65%, AUROC=0.68) resulted in differences that suggest specificity for sertraline treatment compared with placebo treatment. Finally, multimodal models outperformed unimodal models. CONCLUSIONS: The study results confirm that early sertraline treatment response can be predicted; that the models are sertraline specific compared with placebo; that prediction benefits from integrating multimodal MRI data with clinical data; and that perfusion imaging contributes most to these predictions. Using this approach, a lean and effective protocol could individualize sertraline treatment planning to improve psychiatric care.

Improving advanced intraoperative MRI methods during pediatric neurosurgery.

Advanced intraoperative MR images (ioMRI) acquired during the resection of pediatric brain tumors could offer additional physiological information to preserve healthy tissue. With this work, we aimed to develop a protocol for ioMRI with increased sensitivity for arterial spin labeling (ASL) and diffusion MRI (dMRI), optimized for patient positioning regularly used in the pediatric neurosurgery setting. For ethical reasons, ASL images were acquired in healthy adult subjects that were imaged in the prone and supine position. After this, the ASL cerebral blood flow (CBF) was quantified and compared between both positions. To evaluate the impact of the RF coils setups on image quality, we compared different setups (two vs. four RF coils) by looking at T1-weighted (T1w) signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), as well as undertaking a qualitative evaluation of T1w, T2w, ASL, and dMR images. Mean ASL CBF did not differ between the surgical prone and supine positions in any of the investigated regions of interest or the whole brain. T1w SNR (gray matter: p = 0.016, 34% increase; white matter: p = 0.016, 32% increase) and CNR were higher (p = 0.016) in the four versus two RF coils setups (18.0 ± 1.8 vs. 13.9 ± 1.8). Qualitative evaluation of T1w, T2w, ASL, and dMR images resulted in acceptable to good image quality and did not differ statistically significantly between setups. Only the nonweighted diffusion image maps and corticospinal tract reconstructions yielded higher image quality and reduced susceptibility artifacts with four RF coils. Advanced ioMRI metrics were more precise with four RF coils as the standard deviation decreased. Taken together, we have investigated the practical use of advanced ioMRI during pediatric neurosurgery. We conclude that ASL CBF quantification in the surgical prone position is valid and that ASL and dMRI acquisition with two RF coils can be performed adequately for clinical use. With four versus two RF coils, the SNR of the images increases, and the sensitivity to artifacts reduces.

A systematic review of (semi-)automatic quality control of T1-weighted MRI scans.

PURPOSE: Artifacts in magnetic resonance imaging (MRI) scans degrade image quality and thus negatively affect the outcome measures of clinical and research scanning. Considering the time-consuming and subjective nature of visual quality control (QC), multiple (semi-)automatic QC algorithms have been developed. This systematic review presents an overview of the available (semi-)automatic QC algorithms and software packages designed for raw, structural T1-weighted (T1w) MRI datasets. The objective of this review was to identify the differences among these algorithms in terms of their features of interest, performance, and benchmarks. METHODS: We queried PubMed, EMBASE (Ovid), and Web of Science databases on the fifth of January 2023, and cross-checked reference lists of retrieved papers. Bias assessment was performed using PROBAST (Prediction model Risk Of Bias ASsessment Tool). RESULTS: A total of 18 distinct algorithms were identified, demonstrating significant variations in methods, features, datasets, and benchmarks. The algorithms were categorized into rule-based, classical machine learning-based, and deep learning-based approaches. Numerous unique features were defined, which can be roughly divided into features capturing entropy, contrast, and normative measures. CONCLUSION: Due to dataset-specific optimization, it is challenging to draw broad conclusions about comparative performance. Additionally, large variations exist in the used datasets and benchmarks, further hindering direct algorithm comparison. The findings emphasize the need for standardization and comparative studies for advancing QC in MR imaging. Efforts should focus on identifying a dataset-independent measure as well as algorithm-independent methods for assessing the relative performance of different approaches.

Decreased integrity of the monoaminergic tract is associated with a positive response to MPH in patients with vascular cognitive impairment - proof of principle study STREAM-VCI.

Background: Patients with vascular cognitive impairment (VCI) are very heterogeneous in both symptoms and type of cerebrovascular pathology. This might be an important reason why there is no symptomatic treatment available for VCI patients. In this study, we investigated in patients with VCI, whether there was an association between a positive response to methylphenidate and galantamine and the type of cerebrovascular disease, structural damage to specific neurotransmitter systems, cerebral perfusion, and presence of co-morbid Alzheimer (AD) pathology. Methods: We included 27 VCI patients (mean age 67 years ± 8,30% female) from the STREAM-VCI trial who received placebo, methylphenidate(10 mg), and galantamine(16 mg) in a single challenge, cross-over design. In this study, we classified patients improving on a task for executive functioning after methylphenidate compared to placebo as methylphenidate responders (MPH+; resp. non-responders, MPH-) and patients improving on a task for memory after galantamine compared to placebo as galantamine responders (GAL+; resp. non-responders, GAL-). On baseline MRI, we visually assessed measures of cerebrovascular disease, automatically segmented white matter hyperintensities, used diffusion tensor imaging to visualize the integrity of monoaminergic and cholinergic neurotransmitter systems with mean diffusivity (MD) and fractional anisotropy (FA). Comorbid AD pathology was assessed using CSF or amyloid-PET. We tested differences between responders and non-responders using ANOVA, adjusting for age and sex. Results: Nine patients were MPH+ vs 18 MPH-. MPH+ had higher MD (1.22 ± 0.07 vs 0.94 ± 0.05); p = .001) and lower FA (0.38 ± .01 vs 0.43 ± .01); p = .04) in the monoaminergic tract compared to MPH-. Eight patients were GAL+ and 18 GAL-. We found no differences between GAL+ and GAL- in any of the MRI measures. Information on co-morbid AD pathology was present in 17 patients. AD pathology tended to be more frequent in GAL+ vs GAL- (5(71%) vs 2(20%); p = .06). Conclusions: In patients with VCI, we found that decreased integrity of the monoaminergic tract is associated with a positive response to MPH. Responsiveness to galantamine may be related to co-morbid AD pathology.

Safety and efficacy of losartan for the reduction of brain atrophy in clinically diagnosed Alzheimer's disease (the RADAR trial): a double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Drugs modifying angiotensin II signalling could reduce Alzheimer's disease pathology, thus decreasing the rate of disease progression. We investigated whether the angiotensin II receptor antagonist losartan, compared with placebo, could reduce brain volume loss, as a measure of disease progression, in clinically diagnosed mild-to-moderate Alzheimer's disease. METHODS: In this double-blind, multicentre, randomised controlled trial, eligible patients aged 55 years or older, previously untreated with angiotensin II drugs and diagnosed (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria) with mild-to-moderate Alzheimer's disease, and who had capacity to consent, were recruited from 23 UK National Health Service hospital trusts. After undergoing a 4-week, open-label phase of active treatment then washout, participants were randomly assigned (1:1) oral over-encapsulated preparations of either 100 mg losartan (after an initial two-dose titration stage) or matched placebo daily for 12 months. Randomisation, minimised by age and baseline medial temporal lobe atrophy score, was undertaken online or via pin-access service by telephone. Participants, their study companions, and study personnel were masked to group assignment. The primary outcome, analysed by the intention-to-treat principle (ie, participants analysed in the group to which they were randomised, without imputation for missing data), was change in whole brain volume between baseline and 12 months, measured using volumetric MRI and determined by boundary shift interval (BSI) analysis. The trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN93682878) and the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT 2012-003641-15), and is completed. FINDINGS: Between July 22, 2014, and May 17, 2018, 261 participants entered the open-label phase. 211 were randomly assigned losartan (n=105) or placebo (n=106). Of 197 (93%) participants who completed the study, 171 (81%) had complete primary outcome data. The mean brain volume (BSI) reduction was 19·1 mL (SD 10·3) in the losartan group and 20·0 mL (10·8) in the placebo group. The difference in total volume reduction between groups was -2·29 mL (95% CI -6·46 to 0·89; p=0·14). The number of adverse events was low (22 in the losartan group and 20 in the placebo group) with no differences between treatment groups. There was one treatment-related death per treatment group. INTERPRETATION: 12 months of treatment with losartan was well tolerated but was not effective in reducing the rate of brain atrophy in individuals with clinically diagnosed mild-to-moderate Alzheimer's disease. Further research is needed to assess the potential therapeutic benefit from earlier treatment in patients with milder cognitive impairment or from longer treatment periods. FUNDING: Efficacy and Mechanism Evaluation Programme (UK Medical Research Council and National Institute for Health Research).

Normal structural brain development in adolescents treated for perinatally acquired HIV: a longitudinal imaging study.

OBJECTIVE: Cross-sectional studies, including one from our NOVICE cohort [Neurological Visual and Cognitive performance in children with treated perinatally acquired HIV (PHIV) compared with matched HIV-negative controls], have revealed that the brains of children with PHIV have lower white matter and grey matter volumes, more white matter hyperintensities (WMH) and poorer white matter integrity. This longitudinal study investigates whether these differences change over time. METHODS: We approached all NOVICE participants to repeat MRI after 4.6 ±â€Š0.3 years, measuring total white matter and grey matter volume, WMH volume and white matter integrity, obtained by T1-weighted, fluid-attenuated inversion recovery (FLAIR) and diffusion tensor imaging (DTI), respectively. We compared rates of change between groups using multivariable linear mixed effects models, adjusted for sex and age at enrolment. We investigated determinants of developmental deviation, and explored associations with cognitive development. RESULTS: Twenty out of 31 (65%) PHIV-positive, and 20 out of 37 (54%) HIV-negative participants underwent follow-up MRI. Groups did not significantly differ in terms of age and sex. Over time, we found no statistically different changes between groups for white matter and WMH volumes, and for white matter integrity (P > 0.1). Total grey matter volume decreased significantly less in PHIV [group∗time 10 ml, 95% confidence interval -1 to 20, P = 0.078], but this difference in rate of change lost statistical significance after additional adjustment for height (group∗time 9 ml, 95% confidence interval -2 to 20, P = 0.112). We found no HIV-associated determinants for potential reduced grey matter pruning, nor associations with cognitive development. CONCLUSION: While using long-term antiretroviral treatment, structural brain development of adolescents growing up with perinatally acquired HIV appears largely normal.

The Open Brain Consent: Informing research participants and obtaining consent to share brain imaging data.

Having the means to share research data openly is essential to modern science. For human research, a key aspect in this endeavor is obtaining consent from participants, not just to take part in a study, which is a basic ethical principle, but also to share their data with the scientific community. To ensure that the participants' privacy is respected, national and/or supranational regulations and laws are in place. It is, however, not always clear to researchers what the implications of those are, nor how to comply with them. The Open Brain Consent (https://open-brain-consent.readthedocs.io) is an international initiative that aims to provide researchers in the brain imaging community with information about data sharing options and tools. We present here a short history of this project and its latest developments, and share pointers to consent forms, including a template consent form that is compliant with the EU general data protection regulation. We also share pointers to an associated data user agreement that is not only useful in the EU context, but also for any researchers dealing with personal (clinical) data elsewhere.

Cognitive Improvement After Kidney Transplantation Is Associated With Structural and Functional Changes on MRI.

BACKGROUND: Several studies have reported improved cognitive outcomes after kidney transplantation, but most studies either did not include controls or lacked extensive neuroimaging. In addition, there is uncertainty whether kidney donation is a safe procedure in terms of cognitive outcomes. METHODS: We prospectively studied neurocognitive function in kidney transplant recipients. The primary outcome was change in neurocognitive function after 1 year compared with baseline, which was evaluated using the Amsterdam Neuropsychological Task battery and verbal fluency tests. Secondary outcomes included changes in depression and anxiety (measured by the Hospital Anxiety and Depression scale) and changes in fatigue (measured by the Checklist for Individual Strength). We included kidney donors to control for learning effects, socioeconomic status, and surgery. In addition, kidney transplant recipients were evaluated with MRI scans at baseline and at year 1. The MRI protocol included conventional MRI, automated volumetric measurement, diffusion tensor imaging, magnetic resonance spectroscopy, arterial spin labeling, and a resting state functional MRI. RESULTS: Twenty-seven recipients and 24 donors were included. For both recipients and donors, neuropsychologic testing scores improved 1 year after transplantation (donation). Recipient improvement significantly exceeded donor improvement on tasks measuring attention and working memory. These improvements were associated with increases in white matter volume and N-acetylaspartate/creatine (a marker for neuronal integrity). CONCLUSIONS: Attention and working memory improve significantly 1 year after kidney transplantation. Learning effects do not account for these improvements because recipient improvement in these areas exceeds donor improvement and correlates with an improvement in white matter integrity after transplantation. Kidney donation appears to be a safe procedure in terms of cognitive outcomes.

Dose-dependent effects of the selective serotonin reuptake inhibitor citalopram: A combined SPECT and phMRI study.

BACKGROUND: Serotonin transporter blockers, like citalopram, dose-dependently bind to the serotonin transporter. Pharmacological magnetic resonance imaging (phMRI) can be used to non-invasively monitor effects of serotonergic medication. Although previous studies showed that phMRI can measure the effect of a single dose of serotoninergic medication, it is currently unclear whether it can also detect dose-dependent effects. AIMS: To investigate the dose-dependent phMRI response to citalopram and compared this with serotonin transporter occupancy, measured with single photon emission computed tomography (SPECT). METHODS: Forty-five healthy females were randomized to pre-treatment with placebo, a low (4 mg) or clinically standard (16 mg) oral citalopram dose. Prior to citalopram, and 3 h after, subjects underwent SPECT scanning. Subsequently, a phMRI scan with a citalopram challenge (7.5 mg intravenously) was conducted. Change in cerebral blood flow in response to the citalopram challenge was assessed in the thalamus and occipital cortex (control region). RESULTS: Citalopram dose-dependently affected serotonin transporter occupancy, as measured with SPECT. In addition, citalopram dose-dependently affected the phMRI response to intravenous citalopram in the thalamus (but not occipital cortex), but phMRI was less sensitive in distinguishing between groups than SPECT. Serotonin transporter occupancy showed a trend-significant correlation to thalamic cerebral blood flow change. CONCLUSION: These results suggest that phMRI likely suffers from higher variation than SPECT, but that these techniques probably also assess different functional aspects of the serotonergic synapse; therefore phMRI could complement positron emission tomography/SPECT for measuring effects of serotonergic medication.

Variability of physiological brain perfusion in healthy subjects - A systematic review of modifiers. Considerations for multi-center ASL studies.

Quantitative measurements of brain perfusion are influenced by perfusion-modifiers. Standardization of measurement conditions and correction for important modifiers is essential to improve accuracy and to facilitate the interpretation of perfusion-derived parameters. An extensive literature search was carried out for factors influencing quantitative measurements of perfusion in the human brain unrelated to medication use. A total of 58 perfusion modifiers were categorized into four groups. Several factors (e.g., caffeine, aging, and blood gases) were found to induce a considerable effect on brain perfusion that was consistent across different studies; for other factors, the modifying effect was found to be debatable, due to contradictory results or lack of evidence. Using the results of this review, we propose a standard operating procedure, based on practices already implemented in several research centers. Also, a theory of 'deep MRI physiotyping' is inferred from the combined knowledge of factors influencing brain perfusion as a strategy to reduce variance by taking both personal information and the presence or absence of perfusion modifiers into account. We hypothesize that this will allow to personalize the concept of normality, as well as to reach more rigorous and earlier diagnoses of brain disorders.

Investigating the origin and evolution of cerebral small vessel disease: The RUN DMC - InTENse study.

BACKGROUND: Neuroimaging in older adults commonly reveals signs of cerebral small vessel disease (SVD). SVD is believed to be caused by chronic hypoperfusion based on animal models and longitudinal studies with inter-scan intervals of years. Recent imaging evidence, however, suggests a role for acute ischaemia, as indicated by incidental diffusion-weighted imaging lesions (DWI+ lesions), in the origin of SVD. Furthermore, it becomes increasingly recognised that focal SVD lesions likely affect the structure and function of brain areas remote from the original SVD lesion. However, the temporal dynamics of these events are largely unknown. AIMS: (1) To investigate the monthly incidence of DWI+ lesions in subjects with SVD; (2) to assess to which extent these lesions explain progression of SVD imaging markers; (3) to investigate their effects on cortical thickness, structural and functional connectivity and cognitive and motor performance; and (4) to investigate the potential role of the innate immune system in the pathophysiology of SVD. DESIGN/METHODS: The RUN DMC - InTENse study is a longitudinal observational study among 54 non-demented RUN DMC survivors with mild to severe SVD and no other presumed cause of ischaemia. We performed MRI assessments monthly during 10 consecutive months (totalling up to 10 scans per subject), complemented with clinical, motor and cognitive examinations. DISCUSSION: Our study will provide a better understanding of the role of DWI+ lesions in the pathophysiology of SVD and will further unravel the structural and functional consequences and clinical importance of these lesions, with an unprecedented temporal resolution. Understanding the role of acute, potentially ischaemic, processes in SVD may provide new strategies for therapies.

Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial.

IMPORTANCE: Although numerous children receive methylphenidate hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), little is known about age-dependent and possibly lasting effects of methylphenidate on the human dopaminergic system. OBJECTIVES: To determine whether the effects of methylphenidate on the dopaminergic system are modified by age and to test the hypothesis that methylphenidate treatment of young but not adult patients with ADHD induces lasting effects on the cerebral blood flow response to dopamine challenge, a noninvasive probe for dopamine function. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled trial (Effects of Psychotropic Drugs on Developing Brain-Methylphenidate) among ADHD referral centers in the greater Amsterdam area in the Netherlands between June 1, 2011, and June 15, 2015. Additional inclusion criteria were male sex, age 10 to 12 years or 23 to 40 years, and stimulant treatment-naive status. INTERVENTIONS: Treatment with either methylphenidate or a matched placebo for 16 weeks. MAIN OUTCOMES AND MEASURES: Change in the cerebral blood flow response to an acute challenge with methylphenidate, noninvasively assessed using pharmacological magnetic resonance imaging, between baseline and 1 week after treatment. Data were analyzed using intent-to-treat analyses. RESULTS: Among 131 individuals screened for eligibility, 99 patients met DSM-IV criteria for ADHD, and 50 participants were randomized to receive methylphenidate and 49 to placebo. Sixteen weeks of methylphenidate treatment increased the cerebral blood flow response to methylphenidate within the thalamus (mean difference, 6.5; 95% CI, 0.4-12.6; P = .04) of children aged 10 to 12 years old but not in adults or in the placebo group. In the striatum, the methylphenidate condition differed significantly from placebo in children but not in adults (mean difference, 7.7; 95% CI, 0.7-14.8; P = .03). CONCLUSIONS AND RELEVANCE: We confirm preclinical data and demonstrate age-dependent effects of methylphenidate treatment on human extracellular dopamine striatal-thalamic circuitry. Given its societal relevance, these data warrant replication in larger groups with longer follow-up. TRIAL REGISTRATION: identifier: NL34509.000.10 and trialregister.nl identifier: NTR3103.

Cerebral injury in perinatally HIV-infected children compared to matched healthy controls.

OBJECTIVE: The current study aims to evaluate the neurologic state of perinatally HIV-infected children on combination antiretroviral therapy and to attain a better insight into the pathogenesis of their persistent neurologic and cognitive deficits. METHODS: We included perinatally HIV-infected children between 8 and 18 years and healthy controls matched for age, sex, ethnicity, and socioeconomic status. All participants underwent a 3.0 T MRI with 3D-T1-weighted, 3D-fluid-attenuated inversion recovery, and diffusion-weighted series for the evaluation of cerebral volumes, white matter hyperintensities (WMH), and white matter (WM) diffusion characteristics. Associations with disease-related parameters and cognitive performance were explored using linear regression models. RESULTS: We included 35 cases (median age 13.8 years) and 37 controls (median age 12.1 years). A lower gray matter and WM volume, more WMH, and a higher WM diffusivity were observed in the cases. Within the HIV-infected children, a poorer clinical, immunologic, and virologic state were negatively associated with volumetric, WMH, and diffusivity markers. CONCLUSIONS: In children with HIV, even when long-term clinically and virologically controlled, we found lower brain volumes, a higher WMH load, and poorer WM integrity compared to matched controls. These differences occur in the context of a poor cognitive performance in the HIV-infected group, and larger, longitudinal studies are needed to increase our understanding of the pathogenesis of cerebral injury in perinatally HIV-infected children.