Cerebrovascular reactivity MRI as a biomarker for cerebral small vessel disease-related cognitive decline: Multi-site validation in the MarkVCID Consortium.

INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis. METHODS: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes. RESULTS: CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function. DISCUSSION: The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID. HIGHLIGHTS: This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.

Association of Baseline Cerebrovascular Reactivity and Longitudinal Development of Enlarged Perivascular Spaces in the Basal Ganglia.

BACKGROUND: Increasing evidence suggests that enlarged perivascular spaces (ePVS) are associated with cognitive dysfunction in aging. However, the pathogenesis of ePVS remains unknown. Here, we tested the possibility that baseline cerebrovascular dysfunction, as measured by a magnetic resonance imaging measure of cerebrovascular reactivity, contributes to the later development of ePVS. METHODS: Fifty cognitively unimpaired, older adults (31 women; age range, 60-84 years) underwent magnetic resonance imaging scanning at baseline and follow-up separated by ≈2.5 years. ePVS were counted in the basal ganglia, centrum semiovale, midbrain, and hippocampus. Cerebrovascular reactivity, an index of the vasodilatory capacity of cerebral small vessels, was assessed using carbon dioxide inhalation while acquiring blood oxygen level-dependent magnetic resonance images. RESULTS: Low baseline cerebrovascular reactivity values in the basal ganglia were associated with increased follow-up ePVS counts in the basal ganglia after controlling for age, sex, and baseline ePVS values (estimate [SE]=-3.18 [0.96]; P=0.002; [95% CI, -5.11 to -1.24]). This effect remained significant after accounting for self-reported risk factors of cerebral small vessel disease (estimate [SE]=-3.10 [1.00]; P=0.003; [CI, -5.11 to -1.09]) and neuroimaging markers of cerebral small vessel disease (estimate [SE]=-2.72 [0.99]; P=0.009; [CI, -4.71 to -0.73]). CONCLUSIONS: Our results demonstrate that low baseline cerebrovascular reactivity is a risk factor for later development of ePVS.

MRI assessment of cerebral oxygen extraction fraction in the medial temporal lobe.

The medial temporal lobe (MTL) is a key area implicated in many brain diseases, such as Alzheimer's disease. As a functional biomarker, the oxygen extraction fraction (OEF) of MTL may be more sensitive than structural atrophy of MTL, especially at the early stages of diseases. However, there is a lack of non-invasive techniques to measure MTL-OEF in humans. The goal of this work is to develop an MRI technique to assess MTL-OEF in a clinically practical time without using contrast agents. The proposed method measures venous oxygenation (Yv) in the basal veins of Rosenthal (BVs), which are the major draining veins of the MTL. MTL-OEF can then be estimated as the arterio-venous difference in oxygenation. We developed an MRI sequence, dubbed arterial-suppressed accelerated T2-relaxation-under-phase-contrast (AS-aTRUPC), to quantify the blood T2 of the BVs, which was then converted to Yv through a well-established calibration model. MTL-OEF was calculated as (Ya-Yv)/Ya × 100%, where Ya was the arterial oxygenation. The feasibility of AS-aTRUPC to quantify MTL-OEF was evaluated in 16 healthy adults. The sensitivity of AS-aTRUPC in detecting OEF changes was assessed by a caffeine ingestion (200 mg) challenge. For comparison, T2-relaxation-under-spin-tagging (TRUST) MRI, which is a widely used global OEF technique, was also acquired. The dependence of MTL-OEF on age was examined by including another seven healthy elderly subjects. The results showed that in healthy adults, MTL-OEF of the left and right hemispheres were correlated (P=0.005). MTL-OEF was measured to be 23.9±3.6% (mean±standard deviation) and was significantly lower (P<0.0001) than the OEF of 33.3±2.9% measured in superior sagittal sinus (SSS). After caffeine ingestion, there was an absolute percentage increase of 9.1±4.0% in MTL-OEF. Additionally, OEF in SSS measured with AS-aTRUPC showed a strong correlation with TRUST OEF (intra-class correlation coefficient=0.94 with 95% confidence interval [0.91, 0.96]), with no significant bias (P=0.12). MTL-OEF was found to increase with age (MTL-OEF=20.997+0.100 × age; P=0.02). In conclusion, AS-aTRUPC MRI provides non-invasive assessments of MTL-OEF and may facilitate future clinical applications of MTL-OEF as a disease biomarker.

Multifunctional Fluorescent Main-Chain Charged Polyelectrolytes Synthesized by Cascade C-H Activation/Annulation Polymerizations.

Fluorescent polyelectrolytes have attracted enormous attention as functional polymer materials. In contrast with the widely studied conjugated polyelectrolytes with ionic groups in side chains, fluorescent main-chain charged polyelectrolytes (MCCPs) have rarely been explored due to the large synthetic difficulty. Herein, we develop a facile and atom-economical N-heterocyclic carbene-directed cascade C-H activation/annulation polymerization strategy that can transform readily available imidazolium substrates and internal diynes into multifunctional fluorescent MCCPs with complex structures and high molecular weights (absolute Mn up to 135 600) in nearly quantitative yields. The presence of multisubstituted polycyclic N-heteroaromatic cations in polymer backbones endow the obtained MCCPs with excellent solution processability, high thermal stability, and dual-state efficient fluorescence in both solution and aggregate states. Benefiting from the strong electron-withdrawing capability of the cationic heterocycles in main chains, multicolored aggregate-state fluorescence can be readily achieved by modifying the substituents around the cationic ring-fused core. Taking advantage of the good photosensitivity of the fluorescent MCCP thin films, multiscale and high-resolution fluorescent photopatterns with different colors can be facilely prepared with potential applications in optical display devices and anticounterfeiting systems. Moreover, the strong electrostatic interactions of these cationic MCCPs with anionic polyelectrolytes enable them to form multicolored fluorescent interfacial polyelectrolyte complexation microfibers with directly visualized internal structures. Such flexible microfibers can be further made into diversified forms of fiber-based macroscopic patterns or painting.

Two galactinol synthases contribute to the drought response of Camellia sinensis.

MAIN CONCLUSION: CsGolS2-1 and CsGolS2-2 are involved in the transcriptional mechanism and play an important role in the drought response of tea plants. GolS is critical for the biosynthesis of galactinol and has been suggested to contribute to drought tolerance in various plants. However, whether GolS plays a role in drought response and the underlying transcriptional mechanism of GolS genes in response to drought stress in tea plants is still unclear. In this study, we found that drought stress promotes the accumulation of galactinol in tea leaves and that the expression of CsGolS2-1 and CsGolS2-2, which encode proteins capable of catalyzing galactinol biosynthesis, is continuously and dramatically induced by drought stress. Moreover, transgenic Arabidopsis plants expressing CsGolS2-1 and CsGolS2-2 were more drought-tolerant than WT plants, as evidenced by increased cell membrane stability. In addition, the drought-responsive transcription factor CsWRKY2 has been shown to positively regulate the expression of CsGolS2-1 and CsGolS2-2 by directly binding to their promoters. Furthermore, CsVQ9 was found to interact with CsWRKY2 and promote its transcriptional function to activate CsGolS2-1 and CsGolS2-2 expression. Taken together, our findings provide insights not only into the positive role played by CsGolS2-1 and CsGolS2-2 in the drought response of tea plants but also into the transcriptional mechanisms involved.

Altered linear coupling between stimulus-evoked blood flow and oxygen metabolism in the aging human brain.

Neural-vascular coupling (NVC) is the process by which oxygen and nutrients are delivered to metabolically active neurons by blood vessels. Murine models of NVC disruption have revealed its critical role in healthy neural function. We hypothesized that, in humans, aging exerts detrimental effects upon the integrity of the neural-glial-vascular system that underlies NVC. To test this hypothesis, calibrated functional magnetic resonance imaging (cfMRI) was used to characterize age-related changes in cerebral blood flow (CBF) and oxygen metabolism during visual cortex stimulation. Thirty-three younger and 27 older participants underwent cfMRI scanning during both an attention-controlled visual stimulation task and a hypercapnia paradigm used to calibrate the blood-oxygen-level-dependent signal. Measurement of stimulus-evoked blood flow and oxygen metabolism permitted calculation of the NVC ratio to assess the integrity of neural-vascular communication. Consistent with our hypothesis, we observed monotonic NVC ratio increases with increasing visual stimulation frequency in younger adults but not in older adults. Age-related changes in stimulus-evoked cerebrovascular and neurometabolic signal could not fully explain this disruption; increases in stimulus-evoked neurometabolic activity elicited corresponding increases in stimulus-evoked CBF in younger but not in older adults. These results implicate age-related, demand-dependent failures of the neural-glial-vascular structures that comprise the NVC system.

Longitudinal changes in brain oxygen extraction fraction (OEF) in older adults: Relationship to markers of vascular and Alzheimer's pathology.

INTRODUCTION: Oxygen extraction fraction (OEF) reflects the balance between oxygen delivery and consumption. We longitudinally measured OEF in older adults to examine the relationship with markers of Alzheimer's disease (AD) and vascular pathology. METHODS: One hundred thirty-seven participants were studied at two time-points at an interval of 2.16 years. OEF was measured using T2 -relaxation-under-spin-tagging (TRUST) magnetic resonance imaging (MRI). The association between OEF and vascular risks, white matter hyperintensities (WMH), cerebrospinal fluid (CSF) measures of amyloid beta (Aß), total tau (t-tau), and phosphorylated tau 181 (p-tau181) was examined. RESULTS: OEF increased from baseline to follow-up. The increase in OEF was more prominent in individuals with high vascular risks compared to those with low vascular risks, and was associated with progression of vascular risks and the growth in WMH volume. OEF change was not related to CSF markers of AD pathology or their progression. DISCUSSION: Longitudinal OEF change in older adults is primarily related to vascular pathology.

Blood-brain barrier permeability in response to caffeine challenge.

PURPOSE: Caffeine is known to alter brain perfusion by acting as an adenosine antagonist, but its effect on blood-brain barrier (BBB) permeability is not fully elucidated. This study aimed to dynamically monitor BBB permeability to water after a single dose of caffeine tablet using a non-contrast MRI technique. METHODS: Ten young healthy volunteers who were not regular coffee drinkers were studied. The experiment began with a pre-caffeine measurement, followed by four measurements at the post-caffeine stage. Water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST) MRI was used to assess the time dependence of BBB permeability to water following the ingestion of 200 mg caffeine. Other cerebral physiological parameters including cerebral blood flow (CBF), venous oxygenation (Yv ), and cerebral metabolic rate of oxygen (CMRO2 ) were also examined. The relationships between cerebral physiological parameters and time were studied with mixed-effect models. RESULTS: It was found that, after caffeine ingestion, CBF and Yv showed a time-dependent decrease (p < 0.001), while CMRO2 did not change significantly. The fraction of arterial water crossing the BBB (E) showed a significant increase (p < 0.001). In contrast, the permeability-surface-area product (PS), i.e., BBB permeability to water, remained constant (p = 0.94). Additionally, it was observed that changes in physiological parameters were non-linear with regard to time and occurred at as early as 9 min after caffeine tablet ingestion. CONCLUSION: These results suggest an unchanged BBB permeability despite alterations in perfusion during a vasoconstrictive caffeine challenge.

Blood-Brain Barrier Breakdown in Relationship to Alzheimer and Vascular Disease.

OBJECTIVE: Blood-brain barrier (BBB) breakdown has been suggested to be an early biomarker in human cognitive impairment. However, the relationship between BBB breakdown and brain pathology, most commonly Alzheimer disease (AD) and vascular disease, is still poorly understood. The present study measured human BBB function in mild cognitive impairment (MCI) patients on 2 molecular scales, specifically BBB's permeability to water and albumin molecules. METHODS: Fifty-five elderly participants were enrolled, including 33 MCI patients and 22 controls. BBB permeability to water was measured with a new magnetic resonance imaging technique, water extraction with phase contrast arterial spin tagging. BBB permeability to albumin was determined using cerebrospinal fluid (CSF)/serum albumin ratio. Cognitive performance was assessed by domain-specific composite scores. AD pathology (including CSF Aß and ptau) and vascular risk factors were examined. RESULTS: Compared to cognitively normal subjects, BBB in MCI patients manifested an increased permeability to small molecules such as water but was no more permeable to large molecules such as albumin. BBB permeability to water was found to be related to AD markers of CSF Aß and ptau. On the other hand, BBB permeability to albumin was found to be related to vascular risk factors, especially hypercholesterolemia, but was not related to AD pathology. BBB permeability to small molecules, but not to large molecules, was found to be predictive of cognitive function. INTERPRETATION: These findings provide early evidence that BBB breakdown is related to both AD and vascular risks, but their effects can be differentiated by spatial scales. BBB permeability to small molecules has a greater impact on cognitive performance. ANN NEUROL 2021;90:227-238.

Longitudinal Changes in Global Cerebral Blood Flow in Cognitively Normal Older Adults: A Phase-Contrast MRI Study.

BACKGROUND: Characterization of blood supply changes in older individuals is important in understanding brain aging and diseases. However, prior studies largely focused on cross-sectional design, thus change in cerebral blood flow (CBF) could not be assessed on an individual level. PURPOSE: To evaluate longitudinal short-term changes in global CBF in cognitively normal older adults. STUDY TYPE: Prospective, longitudinal, and cohort. POPULATION: One-hundred twenty-seven cognitive-normal participants (mean age 69 ± 7 years, 47 males) underwent serial MRI with an average follow-up time of 2.1 years. FIELD STRENGTH/SEQUENCE: 3 T phase-contrast (PC), three-dimensional magnetization-prepared-rapid-acquisition-of-gradient-echo (MPRAGE) and fluid-attenuated inversion recovery (FLAIR) MRI. ASSESSMENT: Total CBF was measured with PC MRI allowing assessment of quantitative flow in four major feeding arteries by a trained radiologist with >3 years' experience (O.K.). Brain volume was obtained from MPRAGE MRI and measured by T1-MultiAtlas MRICloud tool. The ratio between total CBF and brain volume yielded global CBF in mL/100 g/min. White matter hyperintensity (WMH) was measured automatically using a Bayesian probability approach on FLAIR. STATISTICAL TESTS: Linear mixed effect model was used to simultaneously assess cross-sectional age-differences and longitudinal age-changes in CBF. Spearman rank correlation was used to evaluate the relationship between CBF change and WMH progression. A P-value of <0.05 (two-tailed) was considered significant. RESULTS: Global CBF decreased with age at a longitudinal rate of -0.56 mL/100 g/min/year (95% confidence interval [CI]: -1.09, -0.03), compared to a cross-sectional rate of -0.26 mL/100 g/min/year (95% CI: -0.41, -0.11). Changes in CBF were significantly associated with progression of WMH (Spearman rank correlation r = -0.25), as those participants who had a more rapid CBF reduction had greater increases in WMH volumes and the relationship remained significant when adjusting for baseline vascular risk scores. Additionally, age-related changes in whole-brain volume were found to be -0.151%/year (95% CI: -0.186, -0.116). DATA CONCLUSION: These findings suggest that brain aging in older adults is accompanied by a rapid longitudinal reduction in CBF, the rate of which is associated with white matter damage. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Imaging Blood-Brain Barrier Permeability Through MRI in Pediatric Sickle Cell Disease: A Feasibility Study.

BACKGROUND: Blood-brain barrier (BBB) disruption may lead to endothelium dysfunction and inflammation in sickle cell disease (SCD). However, abnormalities of BBB in SCD, especially in pediatric patients for whom contrast agent administration less than optimal, have not been fully characterized. PURPOSE: To examine BBB permeability to water in a group of pediatric SCD participants using a non-invasive magnetic resonance imaging technique. We hypothesized that SCD participants will have increased BBB permeability. STUDY TYPE: Prospective cross-sectional. POPULATION: Twenty-six pediatric participants (10 ± 1 years, 15F/11M) were enrolled, including 21 SCD participants and 5 sickle cell trait (SCT) participants, who were siblings of SCD patients. FIELD STRENGTH/SEQUENCE: 3 T. Water extraction with phase-contrast arterial spin tagging with echo-planer imaging, phase-contrast and T1 -weighted magnetization-prepared rapid acquisition of gradient echo. ASSESSMENT: Water extraction fraction (E), BBB permeability-surface area product (PS), cerebral blood flow, hematological measures (hemoglobin, hematocrit, hemoglobin S), neuropsychological scores (including domains of intellectual ability, attention and executive function, academic achievement and adaptive function, and a composite score). Regions of interest were drawn by Z.L. (6 years of experience). STATISTICAL TESTS: Wilcoxon rank sum test and chi-square test for group comparison of demographics. Multiple linear regression analysis of PS with diagnostic category (SCD or SCT), hematological measures, and neuropsychological scores. A two-tailed P value of 0.05 or less was considered statistically significant. RESULTS: Compared with SCT participants, SCD participants had a significantly higher BBB permeability to water (SCD: 207.0 ± 33.3 mL/100 g/minute, SCT: 171.2 ± 27.2 mL/100 g/minute). SCD participants with typically more severe phenotypes also had a significantly leakier BBB than those with typically milder phenotypes (severe: 217.3 ± 31.7 mL/100 g/minute, mild: 193.3 ± 31.8 mL/100 g/minute). Furthermore, more severe BBB disruption was associated with worse hematological symptoms, including lower hemoglobin concentrations (ß = -8.84, 95% confidence interval [CI] [-14.69, -3.00]), lower hematocrits (ß = -2.96, 95% CI [-4.84, -1.08]), and higher hemoglobin S fraction (ß = 0.77, 95% CI [0.014, 1.53]). DATA CONCLUSION: These findings support a potential role for BBB dysfunction in SCD pathogenesis of ischemic injury. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Comparison of Sodium-Glucose Cotransporter 2 Inhibitors and Glucagon-like Peptide Receptor Agonists for Atrial Fibrillation in Type 2 Diabetes Mellitus: Systematic Review With Network Meta-analysis of Randomized Controlled Trials.

ABSTRACT: Atrial fibrillation (AF) is a major public health concern with a rising prevalence. Although sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown the respective favorable effects on reducing the occurrence of AF/atrial flutter (AFL), comparative protective AF/AFL effects between above 2 novel antidiabetic agents remain unavailable. Thus, we aimed to evaluate the comparative efficacy of SGLT2is and GLP-1RAs in reducing the risk of AF/AFL in patients with type 2 diabetes and estimate relative rankings of interventions. PubMed, Embase, and ClinicalTrials.gov were searched up to December 1, 2020. All available randomized controlled trials comparing SGLT2is and GLP-1RAs with one another or placebo in patients with type 2 diabetes were included. Pooled results were shown as risk ratios (RRs) with 95% confidence intervals (CIs). We used a frequentist network meta-analysis to evaluate the outcomes of interests. Thirty-six randomized controlled trials including 85,701 participants with type 2 diabetes were identified. Compared with placebo, both SGLT2is (RR: 0.82, 95% CI, 0.68-0.99) and GLP-1RAs (RR: 0.86, 95% CI, 0.76-0.97; RR long-acting ones: 0.87, 95% CI, 0.76-0.99; RR short-acting ones: 0.72, 95% CI, 0.45-1.14) significantly reduced AF/AFL risk. No significant difference between SGLT2is and GLP-1RAs was noted (RR: 0.95, 95% CI, 0.76-1.2). Compared with placebo, results from the analysis showed an RR of 0.72 (95% CI, 0.45-1.14) for short-acting GLP-1RAs and 0.87 (95% CI, 0.76-0.99) for long-acting GLP-1RAs in reducing the risk of AF/AFL. Compared with placebo, both SGLT2is and GLP-1RAs possessed favorable effects on reducing the risk of AF/AFL. However, no difference was observed when comparisons were made between them. In addition, long-acting ones may confer a more pronounced AF/AFL reduction benefit compared with placebo.

The discovery of BMS-737 as a potent, CYP17 lyase-selective inhibitor for the treatment of castration-resistant prostate cancer.

We report herein, the discovery of BMS-737 (compound 33) as a potent, non-steroidal, reversible small molecule inhibitor demonstrating 11-fold selectivity for CYP17 lyase over CYP17 hydroxylase, as well as a clean xenobiotic CYP profile for the treatment of castration-resistant prostate cancer (CRPC). Extensive SAR studies on the initial lead 1 at three different regions of the molecule resulted in the identification of BMS-737, which demonstrated a robust 83% lowering of testosterone without any significant perturbation of the mineralocorticoid and glucocorticoid levels in cynomologous monkeys in a 1-day PK/PD study.

Huntingtin silencing delays onset and slows progression of Huntington's disease: a biomarker study.

Huntington's disease is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the huntingtin (HTT) gene, coding for pathological mutant HTT protein (mHTT). Because of its gain-of-function mechanism and monogenic aetiology, strategies to lower HTT are being actively investigated as disease-modifying therapies. Most approaches are currently targeted at the manifest stage, where clinical outcomes are used to evaluate the effectiveness of therapy. However, as almost 50% of striatal volume has been lost at the time of onset of clinical manifest, it would be preferable to begin therapy in the premanifest period. An unmet challenge is how to evaluate therapeutic efficacy before the presence of clinical symptoms as outcome measures. To address this, we aim to develop non-invasive sensitive biomarkers that provide insight into therapeutic efficacy in the premanifest stage of Huntington's disease. In this study, we mapped the temporal trajectories of arteriolar cerebral blood volumes (CBVa) using inflow-based vascular-space-occupancy (iVASO) MRI in the heterozygous zQ175 mice, a full-length mHTT expressing and slowly progressing model with a premanifest period as in human Huntington's disease. Significantly elevated CBVa was evident in premanifest zQ175 mice prior to motor deficits and striatal atrophy, recapitulating altered CBVa in human premanifest Huntington's disease. CRISPR/Cas9-mediated non-allele-specific HTT silencing in striatal neurons restored altered CBVa in premanifest zQ175 mice, delayed onset of striatal atrophy, and slowed the progression of motor phenotype and brain pathology. This study-for the first time-shows that a non-invasive functional MRI measure detects therapeutic efficacy in the premanifest stage and demonstrates long-term benefits of a non-allele-selective HTT silencing treatment introduced in the premanifest Huntington's disease.

Multi-vendor and multisite evaluation of cerebrovascular reactivity mapping using hypercapnia challenge.

Cerebrovascular reactivity (CVR), which measures the ability of cerebral blood vessels to dilate or constrict in response to vasoactive stimuli such as CO2 inhalation, is an important index of the brain's vascular health. Quantification of CVR using BOLD MRI with hypercapnia challenge has shown great promises in research and clinical studies. However, in order for it to be used as a potential imaging biomarker in large-scale and multi-site studies, the reliability of CO2-CVR quantification across different MRI acquisition platforms and researchers/raters must be examined. The goal of this report from the MarkVCID small vessel disease biomarkers consortium is to evaluate the reliability of CO2-CVR quantification in three studies. First, the inter-rater reliability of CO2-CVR data processing was evaluated by having raters from 5 MarkVCID sites process the same 30 CVR datasets using a cloud-based CVR data processing pipeline. Second, the inter-scanner reproducibility of CO2-CVR quantification was assessed in 10 young subjects across two scanners of different vendors. Third, test-retest repeatability was evaluated in 20 elderly subjects from 4 sites with a scan interval of less than 2 weeks. In all studies, the CO2 CVR measurements were performed using the fixed inspiration method, where the subjects wore a nose clip and a mouthpiece and breathed room air and 5% CO2 air contained in a Douglas bag alternatively through their mouth. The results showed that the inter-rater CoV of CVR processing was 0.08 ± 0.08% for whole-brain CVR values and ranged from 0.16% to 0.88% in major brain regions, with ICC of absolute agreement above 0.9959 for all brain regions. Inter-scanner CoV was found to be 6.90 ± 5.08% for whole-brain CVR values, and ranged from 4.69% to 12.71% in major brain regions, which are comparable to intra-session CoVs obtained from the same scanners on the same day. ICC of consistency between the two scanners was 0.8498 for whole-brain CVR and ranged from 0.8052 to 0.9185 across major brain regions. In the test-retest evaluation, test-retest CoV across different days was found to be 18.29 ± 17.12% for whole-brain CVR values, and ranged from 16.58% to 19.52% in major brain regions, with ICC of absolute agreement ranged from 0.6480 to 0.7785. These results demonstrated good inter-rater, inter-scanner, and test-retest reliability in healthy volunteers, and suggested that CO2-CVR has suitable instrumental properties for use as an imaging biomarker of cerebrovascular function in multi-site and longitudinal observational studies and clinical trials.

Cerebrovascular Reactivity Mapping Using Resting-State BOLD Functional MRI in Healthy Adults and Patients with Moyamoya Disease.

Background Cerebrovascular reserve, the potential capacity of brain tissue to receive more blood flow when needed, is a desirable marker in evaluating ischemic risk. However, current measurement methods require acetazolamide injection or hypercapnia challenge, prompting a clinical need for resting-state (RS) blood oxygen level-dependent (BOLD) functional MRI data to measure cerebrovascular reactivity (CVR). Purpose To optimize and evaluate an RS CVR MRI technique and demonstrate its relationship to neurosurgical treatment. Materials and Methods In this HIPAA-compliant study, RS BOLD functional MRI data collected in 170 healthy controls between December 2008 and September 2010 were retrospectively evaluated to identify the optimal frequency range of temporal filtering on the basis of spatial correlation with the reference standard CVR map obtained with CO2 inhalation. Next, the optimized RS method was applied in a new, prospective cohort of 50 participants with Moyamoya disease who underwent imaging between June 2014 and August 2019. Finally, CVR values were compared between brain hemispheres with and brain hemispheres without revascularization surgery by using Mann-Whitney U test. Results A total of 170 healthy controls (mean age ± standard deviation, 51 years ± 20; 105 women) and 100 brain hemispheres of 50 participants with Moyamoya disease (mean age, 41 years ± 12; 43 women) were evaluated. RS CVR maps based on a temporal filtering frequency of [0, 0.1164 Hz] yielded the highest spatial correlation (r = 0.74) with the CO2 inhalation CVR results. In patients with Moyamoya disease, 77 middle cerebral arteries (MCAs) had stenosis. RS CVR in the MCA territory was lower in the group that did not undergo surgery (n = 30) than in the group that underwent surgery (n = 47) (mean, 0.407 relative units [ru] ± 0.208 vs 0.532 ru ± 0.182, respectively; P = .006), which is corroborated with the CO2 inhalation CVR data (mean, 0.242 ru ± 0.273 vs 0.437 ru ± 0.200; P = .003). Conclusion Cerebrovascular reactivity mapping performed by using resting-state blood oxygen level-dependent functional MRI provided a task-free method to measure cerebrovascular reserve and depicted treatment effect of revascularization surgery in patients with Moyamoya disease comparable to that with the reference standard of CO2 inhalation MRI. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Wolf and Ware in this issue.

Multi-band MR fingerprinting (MRF) ASL imaging using artificial-neural-network trained with high-fidelity experimental data.

PURPOSE: We aim to leverage the power of deep-learning with high-fidelity training data to improve the reliability and processing speed of hemodynamic mapping with MR fingerprinting (MRF) arterial spin labeling (ASL). METHODS: A total of 15 healthy subjects were studied on a 3T MRI. Each subject underwent 10 runs of a multi-band multi-slice MRF-ASL sequence for a total scan time of approximately 40 min. MRF-ASL images were averaged across runs to yield a set of high-fidelity data. Training of a fully connected artificial neural network (ANN) was then performed using these data. The results from ANN were compared to those of dictionary matching (DM), ANN trained with single-run experimental data and with simulation data. Initial clinical performance of the technique was also demonstrated in a Moyamoya patient. RESULTS: The use of ANN reduced the processing time of MRF-ASL data to 3.6 s, compared to DM of 3 h 12 min. Parametric values obtained with ANN and DM were strongly correlated (R2 between 0.84 and 0.96). Results obtained from high-fidelity ANN were substantially more reliable compared to those from DM or single-run ANN. Voxel-wise coefficient of variation (CoV) of high-fidelity ANN, DM, and single-run ANN was 0.15 ± 0.08, 0.41 ± 0.20, 0.30 ± 0.16, respectively, for cerebral blood flow and 0.11 ± 0.06, 0.20 ± 0.19, 0.15 ± 0.10, respectively, for bolus arrival time. In vivo data trained ANN also outperformed ANN trained with simulation data. The superior performance afforded by ANN allowed more conspicuous depiction of hemodynamic abnormalities in Moyamoya patient. CONCLUSION: Deep-learning-based parametric reconstruction improves the reliability of MRF-ASL hemodynamic maps and reduces processing time.

Quantitative validation of MRI mapping of cerebral venous oxygenation with direct blood sampling: A graded-O2 study in piglets.

PURPOSE: To validate two neonatal cerebral venous oxygenation (Yv ) MRI techniques, T2 relaxation under phase contrast (TRUPC) and accelerated TRUPC (aTRUPC) MRI, with oxygenation measured with direct blood sampling. METHODS: In vivo experiments were performed on seven healthy newborn piglets. For each piglet, a catheter was placed in the superior sagittal sinus to obtain venous blood samples for blood gas oximetry measurement as a gold standard. During the MRI experiment, three to five venous oxygenation levels were achieved in each piglet by varying inhaled O2 content and breathing rate. Under each condition, Yv values of the superior sagittal sinus measured by TRUPC, aTRUPC, and blood gas oximetry were obtained. The Yv quantification in TRUPC and aTRUPC used a standard bovine blood calibration model. The aTRUPC scan was repeated twice to assess its reproducibility. Agreements among TRUPC Yv , aTRUPC Yv , and blood gas oximetry were evaluated by intraclass correlation coefficient (ICC) and paired Student's t-test. RESULTS: The mean hematocrit was 23.6 ± 6.5% among the piglets. Across all measurements, Yv values were 51.9 ± 21.3%, 54.1 ± 18.8%, and 53.7 ± 19.2% for blood gas oximetry, TRUPC and aTRUPC, respectively, showing no significant difference between any two methods (P > .3). There were good correlations between TRUPC and blood gas Yv (ICC = 0.801; P < .0001), between aTRUPC and blood gas Yv (ICC = 0.809; P < .0001), and between aTRUPC and TRUPC Yv (ICC = 0.887; P < .0001). The coefficient of variation of aTRUPC Yv was 8.1 ± 9.9%. CONCLUSION: The values of Yv measured by TRUPC and aTRUPC were in good agreement with blood gas oximetry. These findings suggest that TRUPC and aTRUPC can provide accurate quantifications of Yv in major cerebral veins.

Multi-Parametric Evaluation of Cerebral Hemodynamics in Neonatal Piglets Using Non-Contrast-Enhanced Magnetic Resonance Imaging Methods.

BACKGROUND: Disruption of brain oxygen delivery and consumption after hypoxic-ischemic injury contributes to neonatal mortality and neurological impairment. Measuring cerebral hemodynamic parameters, including cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2 ), is clinically important. PURPOSE: Phase-contrast (PC), velocity-selective arterial spin labeling (VSASL), and T2 -relaxation-under-phase-contrast (TRUPC) are magnetic resonance imaging (MRI) techniques that have shown promising results in assessing cerebral hemodynamics in humans. We aimed to test their feasibility in quantifying CBF, OEF, and CMRO2 in piglets. STUDY TYPE: Prospective. ANIMAL MODEL: Ten neonatal piglets subacutely recovered from global hypoxia-ischemia (N = 2), excitotoxic brain injury (N = 6), or sham procedure (N = 2). FIELD STRENGTH/SEQUENCE: VSASL, TRUPC, and PC MRI acquired at 3.0 T. ASSESSMENT: Regional CBF was measured by VSASL. Global CBF was quantified by both PC and VSASL. TRUPC assessed OEF at the superior sagittal sinus (SSS) and internal cerebral veins (ICVs). CMRO2 was calculated from global CBF and SSS-derived OEF. End-tidal carbon dioxide (EtCO2 ) levels of the piglets were also measured. Brain damage was assessed in tissue sections postmortem by counting damaged neurons. STATISTICAL TESTS: Spearman correlations were performed to evaluate associations among CBF (by PC or VSASL), OEF, CMRO2 , EtCO2 , and the pathological neuron counts. Paired t-test was used to compare OEF at SSS with OEF at ICV. RESULTS: Global CBF was 32.1 ± 14.9 mL/100 g/minute and 30.9 ± 8.3 mL/100 g/minute for PC and VSASL, respectively, showing a significant correlation (r = 0.82, P < 0.05). OEF was 54.9 ± 8.8% at SSS and 46.1 ± 5.6% at ICV, showing a significant difference (P < 0.05). Global CMRO2 was 79.1 ± 26.2 µmol/100 g/minute and 77.2 ± 12.2 µmol/100 g/minute using PC and VSASL-derived CBF, respectively. EtCO2 correlated positively with PC-based CBF (r = 0.81, P < 0.05) but negatively with OEF at SSS (r = -0.84, P < 0.05). Relative CBF of subcortical brain regions and OEF at ICV did not significantly correlate, respectively, with the ratios of degenerating-to-total neurons (P = 0.30, P = 0.10). DATA CONCLUSION: Non-contrast MRI can quantify cerebral hemodynamic parameters in normal and brain-injured neonatal piglets. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Discovery and replication of cerebral blood flow differences in major depressive disorder.

Major depressive disorder (MDD) is a serious, heterogeneous disorder accompanied by brain-related changes, many of which are still to be discovered or refined. Arterial spin labeling (ASL) is a neuroimaging technique used to measure cerebral blood flow (CBF; perfusion) to understand brain function and detect differences among groups. CBF differences have been detected in MDD, and may reveal biosignatures of disease-state. The current work aimed to discover and replicate differences in CBF between MDD participants and healthy controls (HC) as part of the EMBARC study. Participants underwent neuroimaging at baseline, prior to starting study medication, to investigate biosignatures in MDD. Relative CBF (rCBF) was calculated and compared between 106 MDD and 36 HC EMBARC participants (whole-brain Discovery); and 58 MDD EMBARC participants and 58 HC from the DLBS study (region-of-interest Replication). Both analyses revealed reduced rCBF in the right parahippocampus, thalamus, fusiform and middle temporal gyri, as well as the left and right insula, for those with MDD relative to HC. Both samples also revealed increased rCBF in MDD relative to HC in both the left and right inferior parietal lobule, including the supramarginal and angular gyri. Cingulate and prefrontal regions did not fully replicate. Lastly, significant associations were detected between rCBF in replicated regions and clinical measures of MDD chronicity. These results (1) provide reliable evidence for ASL in detecting differences in perfusion for multiple brain regions thought to be important in MDD, and (2) highlight the potential role of using perfusion as a biosignature of MDD.