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Objective: We hypothesised that a multi-compartment magnetic resonance imaging (MRI) technique that is sensitive to fetal blood oxygenation would identify changes in placental blood volume and fetal blood oxygenation in pregnancies complicated by early-onset fetal growth restriction (FGR).Design: Case-control study.Setting: London, UK.Population: Women with uncomplicated pregnancies (estimated fetal weight [EFW] >10th centile for gestational age [GA] and normal maternal and fetal Doppler ultrasound, n = 12) or early-onset FGR (EFW <3rd centile with or without abnormal Doppler ultrasound <32 weeks GA, n = 12) were studied.Methods: All women underwent MRI examination. Using a multi-compartment MRI technique, we quantified fetal and maternal blood volume and feto-placental blood oxygenation.Main Outcome Measures: Disease severity was stratified according to Doppler pulsatility index and the relationship to the MRI parameters was investigated, including the influence of GA at scan.Results: The FGR group (mean GA 27+5  weeks, range 24+2 to 33+6  weeks) had a significantly lower EFW compared with the control group (mean GA 29+1  weeks; -705 g, 95% CI -353 to -1057 g). MRI-derived feto-placental oxygen saturation was higher in controls compared with FGR (75 ± 9.6% versus 56 ± 16.2%, P = 0.02, 95% CI 7.8-30.3%). Feto-placental oxygen saturation estimation correlated strongly with GA at scan in controls (r = -0.83).Conclusion: Using a novel multimodal MRI protocol we demonstrated reduced feto-placental blood oxygen saturation in pregnancies complicated by early-onset FGR. The degree of abnormality correlated with disease severity defined by ultrasound Doppler findings. Gestational age-dependent changes in oxygen saturation were also present in normal pregnancies.Tweetable Abstract: MRI reveals differences in feto-placental oxygen saturation between normal and FGR pregnancy that is associated with disease severity. [ABSTRACT FROM AUTHOR]

Background and Purpose: Incidental findings on brain MRI and variations of the circle of Willis (CoW) are relatively common among the general population. Ethnic differences have been described before, but few studies have explored the prevalence of incidental intracranial cerebrovascular findings and CoW variants in the setting of a single multiethnic cohort. The purpose of this investigation was to describe both incidental cerebrovascular findings and the morphology of the CoW on high-resolution 3T TOF-MRA in a UK tri-ethnic population-based cohort and to present updated prevalence estimates and morphologic reference values., Materials and Methods: We studied participants from the UK Southall and Brent REvisited study who underwent 3T brain MRI between 2014 and 2018. TOF-MRA images were assessed for the presence of incidental cerebrovascular findings and used to determine CoW anatomy., Results: Seven hundred fifty participants (mean age, 71.28 [SD, 6.46] years; range, 46-90 years; 337 women), 322 White Europeans, 253 South Asians, and 175 African Caribbeans were included. Incidental cerebrovascular findings were observed in 84 subjects (11.2%, 95% CI, 9.0%-13.7%; 36 women; 42.86%, 95% CI, 32.11%-54.12%), with cerebral aneurysms being the most frequent followed by intracranial arterial stenoses with the highest prevalence among South Asians compared with White European (OR: 2.72; 95% CI, 1.22-6.08; P = .015) and African Caribbean subjects (OR: 2.79; 95% CI, 1.00-7.82; P = .051). Other findings included arteriovenous malformations and infundibula. The CoW was found to be more often complete in women than in men (25.22% compared with 18.41%, P = .024) and in African Caribbean (34.86%) compared with White European (19.19%) and South Asian (14.23%) subjects ( P < .001 each)., Conclusions: Intracranial arterial stenoses were independently associated with ethnicity after adjusting for vascular risk factors, having the highest prevalence among South Asians. The prevalence of aneurysms was higher than that in previous population-based studies. We observed anatomic differences in the CoW configuration among women, men, and ethnicities., (© 2024 by American Journal of Neuroradiology.)

Purpose: Carotid intraplaque hemorrhage (IPH) on MRI predicts stroke. Magnetization-prepared rapid acquisition gradient (MP-RAGE) is widely used to detect IPH. CE-MRA is used routinely to assess stenosis. Initial studies indicated that IPH can be identified on mask images of CE-MRA, while Time-of-Flight (TOF) images were reported to have high specificity but lower sensitivity. We investigated the diagnostic accuracy of detecting IPH on mask images of CE-MRA and TOF., Methods: Thirty-six patients with ≥ 50% stenosis enrolled in the ongoing 2nd European Carotid Surgery Trial underwent carotid MRI. A 5-point quality score was used. Inter-observer agreement between two independent readers was determined. The sensitivity and specificity of IPH detection on mask MRA and TOF were calculated with MP-RAGE as a reference standard., Results: Of the 36 patients included in the current analysis, 66/72 carotid arteries could be scored. The inter-observer agreements for identifying IPH on MP-RAGE, mask, and TOF were outstanding (κ: 0.93, 0.96, and 0.85). The image quality of mask (1.42 ± 0.66) and TOF (2.42 ± 0.66) was significantly lower than MP-RAGE (3.47 ± 0.61). When T1w images were used to delineate the outer carotid wall, very high specificities (>95%) of IPH detection on mask and TOF images were found, while the sensitivity was high for mask images (>81%) and poor for TOF (50-60%). Without these images, the specificity was still high (>97%), while the sensitivity reduced to 62-71%., Conclusion: Despite the lower image quality, routinely acquired mask images from CE-MRA, but not TOF, can be used as an alternative to MP-RAGE images to visualize IPH., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Opportunities for adjunct therapies with cooling in neonatal encephalopathy are imminent; however, robust biomarkers of early assessment are lacking. Using an optical platform of broadband near-infrared spectroscopy and diffuse correlation spectroscopy to directly measure mitochondrial metabolism (oxCCO), oxygenation (HbD), cerebral blood flow (CBF), we hypothesised optical indices early (1-h post insult) after hypoxia-ischaemia (HI) predicts insult severity and outcome., Methods: Nineteen newborn large white piglets underwent continuous neuromonitoring as controls or following moderate or severe HI. Optical indices were expressed as mean semblance (phase difference) and coherence (spectral similarity) between signals using wavelet analysis. Outcome markers included the lactate/N-acetyl aspartate (Lac/NAA) ratio at 6 h on proton MRS and TUNEL cell count., Results: CBF-HbD semblance (cerebrovascular dysfunction) correlated with BGT and white matter (WM) Lac/NAA (r 2  = 0.46, p = 0.004, r 2  = 0.45, p = 0.004, respectively), TUNEL cell count (r 2  = 0.34, p = 0.02) and predicted both initial insult (r 2  = 0.62, p = 0.002) and outcome group (r 2  = 0.65 p = 0.003). oxCCO-HbD semblance (cerebral metabolic dysfunction) correlated with BGT and WM Lac/NAA (r 2  = 0.34, p = 0.01 and r 2  = 0.46, p = 0.002, respectively) and differentiated between outcome groups (r 2  = 0.43, p = 0.01)., Conclusion: Optical markers of both cerebral metabolic and vascular dysfunction 1 h after HI predicted injury severity and subsequent outcome in a pre-clinical model., Impact: This study highlights the possibility of using non-invasive optical biomarkers for early assessment of injury severity following neonatal encephalopathy, relating to the outcome. Continuous cot-side monitoring of these optical markers can be useful for disease stratification in the clinical population and for identifying infants who might benefit from future adjunct neuroprotective therapies beyond cooling., (© 2023. The Author(s).)

Introduction: Comprehensive imaging using ultrasound and MRI of placenta accreta spectrum (PAS) aims to prevent catastrophic haemorrhage and maternal death. Standard MRI of the placenta is limited by between-slice motion which can be mitigated by super-resolution reconstruction (SRR) MRI. We applied SRR in suspected PAS cases to determine its ability to enhance anatomical placental assessment and predict adverse maternal outcome., Methods: Suspected PAS patients (n = 22) underwent MRI at a gestational age (weeks + days) of (32 +3 ±3 +2 , range (27 +1 -38 +6 )). SRR of the placental-myometrial-bladder interface involving rigid motion correction of acquired MRI slices combined with robust outlier detection to reconstruct an isotropic high-resolution volume, was achieved in twelve. 2D MRI or SRR images alone, and paired data were assessed by four radiologists in three review rounds. All radiologists were blinded to results of the ultrasound, original MR image reports, case outcomes, and PAS diagnosis. A Random Forest Classification model was used to highlight the most predictive pathological MRI markers for major obstetric haemorrhage (MOH), bladder adherence (BA), and placental attachment depth (PAD)., Results: At delivery, four patients had placenta praevia with no abnormal attachment, two were clinically diagnosed with PAS, and six had histopathological PAS confirmation. Pathological MRI markers (T2-dark intraplacental bands, and loss of retroplacental T2-hypointense line) predicting MOH were more visible using SRR imaging (accuracy 0.73), in comparison to 2D MRI or paired imaging. Bladder wall interruption, predicting BA, was only easily detected by paired imaging (accuracy 0.72). Better detection of certain pathological markers predicting PAD was found using 2D MRI (placental bulge and myometrial thinning (accuracy 0.81)), and SRR (loss of retroplacental T2-hypointense line (accuracy 0.82))., Discussion: The addition of SRR to 2D MRI potentially improved anatomical assessment of certain pathological MRI markers of abnormal placentation that predict maternal morbidity which may benefit surgical planning., Competing Interests: Declaration of competing interest None, (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: Cerebral hypoperfusion has been reported in patients with COVID-19 and neurological manifestations in small cohorts. We aimed to systematically assess changes in cerebral perfusion in a cohort of 59 of these patients, with or without abnormalities on morphological MRI sequences., Methods: Patients with biologically-confirmed COVID-19 and neurological manifestations undergoing a brain MRI with technically adequate arterial spin labeling (ASL) perfusion were included in this retrospective multicenter study. ASL maps were jointly reviewed by two readers blinded to clinical data. They assessed abnormal perfusion in four regions of interest in each brain hemisphere: frontal lobe, parietal lobe, posterior temporal lobe, and temporal pole extended to the amygdalo-hippocampal complex., Results: Fifty-nine patients (44 men (75%), mean age 61.2 years) were included. Most patients had a severe COVID-19, 57 (97%) needed oxygen therapy and 43 (73%) were hospitalized in intensive care unit at the time of MRI. Morphological brain MRI was abnormal in 44 (75%) patients. ASL perfusion was abnormal in 53 (90%) patients, and particularly in all patients with normal morphological MRI. Hypoperfusion occurred in 48 (81%) patients, mostly in temporal poles (52 (44%)) and frontal lobes (40 (34%)). Hyperperfusion occurred in 9 (15%) patients and was closely associated with post-contrast FLAIR leptomeningeal enhancement (100% [66.4%-100%] of hyperperfusion with enhancement versus 28.6% [16.6%-43.2%] without, p = 0.002). Studied clinical parameters (especially sedation) and other morphological MRI anomalies had no significant impact on perfusion anomalies., Conclusion: Brain ASL perfusion showed hypoperfusion in more than 80% of patients with severe COVID-19, with or without visible lesion on conventional MRI abnormalities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

MRI assessment of the fetus using fast T 2 -weighted sequences is well established in defining alterations in fetal anatomy and structure, as a biomarker for disease, and in some cases prognostication. To date, the physiological assessment of the fetus using advanced sequences to characterise tissue perfusion and microarchitecture has largely been unused. Current methods of assessing fetal organ function are invasive and carry inherent risk. Therefore, the identification of imaging biomarkers of altered fetal physiology, and correlation with postnatal outcome, is attractive. This review describes the techniques which show promise for such a task and potential future directions.

This 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 ASL consensus paper. Although 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 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, brain tumors, neurodegenerative disease, seizures/epilepsy, and pediatric neuroradiology applications, focusing on disease-specific considerations for sequence optimization and interpretation. We present several neuroradiological applications in which ASL provides unique information essential for making the diagnosis. 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., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Perinatal inflammation combined with hypoxia-ischemia (HI) exacerbates injury in the developing brain. Therapeutic hypothermia (HT) is standard care for neonatal encephalopathy; however, its benefit in inflammation-sensitized HI (IS-HI) is unknown., Methods: Twelve newborn piglets received a 2 µg/kg bolus and 1 µg/kg/h infusion over 52 h of Escherichia coli lipopolysaccharide (LPS). HI was induced 4 h after LPS bolus. After HI, piglets were randomized to HT (33.5 °C 1-25 h after HI, n = 6) or normothermia (NT, n = 6). Amplitude-integrated electroencephalogram (aEEG) was recorded and magnetic resonance spectroscopy (MRS) was acquired at 24 and 48 h. At 48 h, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive brain cell death, microglial activation/proliferation, astrogliosis, and cleaved caspase-3 (CC3) were quantified. Hematology and plasma cytokines were serially measured., Results: Two HT piglets died. aEEG recovery, thalamic and white matter MRS lactate/N-acetylaspartate, and TUNEL-positive cell death were similar between groups. HT increased microglial activation in the caudate, but had no other effect on glial activation/proliferation. HT reduced CC3 overall. HT suppressed platelet count and attenuated leukocytosis. Cytokine profile was unchanged by HT., Conclusions: We did not observe protection with HT in this piglet IS-HI model based on aEEG, MRS, and immunohistochemistry. Immunosuppressive effects of HT and countering neuroinflammation by LPS may contribute to the observed lack of HT efficacy. Other immunomodulatory strategies may be more effective in IS-HI., Impact: Acute infection/inflammation is known to exacerbate perinatal brain injury and can worsen the outcomes in neonatal encephalopathy. Therapeutic HT is the current standard of care for all infants with NE, but the benefit in infants with coinfection/inflammation is unknown. In a piglet model of inflammation (LPS)-sensitized HI, we observed no evidence of neuroprotection with cooling for 24 h, based on our primary outcome measures: aEEG, MRS Lac/NAA, and histological brain cell death. Additional neuroprotective agents, with beneficial immunomodulatory effects, require exploration in IS-HI models., (© 2021. The Author(s).)

Purpose: Intra-arterial Digital Subtraction Angiography (DSA) is the gold standard technique for radiosurgery target delineation in brain Arterio-Venous Malformations (AVMs). This study aims to evaluate whether a combination of three Magnetic Resonance Angiography sequences (triple-MRA) could be used for delineation of brain AVMs for Gamma Knife Radiosurgery (GKR)., Methods: Fifteen patients undergoing DSA for GKR targeting of brain AVMs also underwent triple-MRA: 4D Arterial Spin Labelling based angiography (ASL-MRA), Contrast-Enhanced Time-Resolved MRA (CE-MRA) and High Definition post-contrast Time-Of-Flight angiography (HD-TOF). The arterial phase of the AVM nidus was delineated on triple-MRA by an interventional neuroradiologist and a consultant neurosurgeon (triple-MRA volume). Triple-MRA volumes were compared to AVM targets delineated by the clinical team for delivery of GKR using the current planning paradigm, i.e., stereotactic DSA and volumetric MRI (DSA volume). Difference in size, degree of inclusion (DI) and concordance index (CcI) between DSA and triple-MRA volumes are reported., Results: AVM target volumes delineated on triple-MRA were on average 9.8% smaller than DSA volumes (95%CI:5.6-13.9%; SD:7.14%; p  = .003). DI of DSA volume in triple-MRA volume was on average 73.5% (95%CI:71.2-76; range: 65-80%). The mean percentage of triple-MRA volume not included on DSA volume was 18% (95%CI:14.7-21.3; range: 7-30%)., Conclusion: The technical feasibility of using triple-MRA for visualisation and delineation of brain AVMs for GKR planning has been demonstrated. Tighter and more precise delineation of AVM target volumes could be achieved by using triple-MRA for radiosurgery targeting. However, further research is required to ascertain the impact this may have in obliteration rates and side effects.

Objective: Reliable airway patency diagnosis in fetal tracheolaryngeal obstruction is crucial to select and plan ex utero intrapartum treatment (EXIT) surgery. We compared the clinical utility of magnetic resonance imaging (MRI) super-resolution reconstruction (SRR) of the trachea, which can mitigate unpredictable fetal motion effects, with standard 2-dimensional (2D) MRI for airway patency diagnosis and assessment of fetal neck mass anatomy., Study Design: A single-center case series of 7 consecutive singleton pregnancies with complex upper airway obstruction (2013-2019)., Setting: A tertiary fetal medicine unit performing EXIT surgery., Methods: MRI SRR of the trachea was performed involving rigid motion correction of acquired 2D MRI slices combined with robust outlier detection to reconstruct an isotropic high-resolution volume. SRR, 2D MRI, and paired data were blindly assessed by 3 radiologists in 3 experimental rounds., Results: Airway patency was correctly diagnosed in 4 of 7 cases (57%) with 2D MRI as compared with 2 of 7 cases (29%) with SRR alone or paired 2D MRI and SRR. Radiologists were more confident ( P = .026) in airway patency diagnosis when using 2D MRI than SRR. Anatomic clarity was higher with SRR ( P = .027) or paired data ( P = .041) in comparison with 2D MRI alone. Radiologists detected further anatomic details by using paired images versus 2D MRI alone ( P < .001). Cognitive load, as assessed by the NASA Task Load Index, was increased with paired or SRR data in comparison with 2D MRI., Conclusion: The addition of SRR to 2D MRI does not increase fetal airway patency diagnostic accuracy but does provide improved anatomic information, which may benefit surgical planning of EXIT procedures., (© The Authors 2021.)

Objective: Early prediction of neurological deficits following neonatal hypoxic-ischemic encephalopathy (HIE) may help to target support. Neonatal animal models suggest that recovery following hypoxia-ischemia depends upon cortical bursting. To test whether this holds in human neonates, we correlated the magnitude of cortical bursting during recovery (≥postnatal day 3) with neurodevelopmental outcomes., Methods: We identified 41 surviving infants who received therapeutic hypothermia for HIE (classification at hospital discharge: 19 mild, 18 moderate, 4 severe) and had 9-channel electroencephalography (EEG) recordings as part of their routine care. We correlated burst power with Bayley-III cognitive, motor and language scores at median 24 months. To examine whether EEG offered additional prognostic information, we controlled for structural MRI findings., Results: Higher power of central and occipital cortical bursts predicted worse cognitive and language outcomes, and higher power of central cortical bursts predicted worse motor outcome, all independently of structural MRI findings., Conclusions: Clinical EEG after postnatal day 3 may provide additional prognostic information by indexing persistent active mechanisms that either support recovery or exacerbate brain damage, especially in infants with less severe encephalopathy., Significance: These findings could allow for the effect of clinical interventions in the neonatal period to be studied instantaneously in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: With therapeutic hypothermia (HT) for neonatal encephalopathy, disability rates are reduced, but not all babies benefit. Pre-clinical rodent studies suggest mesenchymal stromal cells (MSCs) augment HT protection., Aims: The authors studied the efficacy of intravenous (IV) or intranasal (IN) human umbilical cord-derived MSCs (huMSCs) as adjunct therapy to HT in a piglet model., Methods: A total of 17 newborn piglets underwent transient cerebral hypoxia-ischemia (HI) and were then randomized to (i) HT at 33.5°C 1-13 h after HI (n = 7), (ii) HT+IV huMSCs (30 × 10 6 cells) at 24 h and 48 h after HI (n = 5) or (iii) HT+IN huMSCs (30 × 10 6 cells) at 24 h and 48 h after HI (n = 5). Phosphorus-31 and hydrogen-1 magnetic resonance spectroscopy (MRS) was performed at 30 h and 72 h and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and oligodendrocytes quantified. In two further piglets, 30 × 10 6 IN PKH-labeled huMSCs were administered., Results: HI severity was similar between groups. Amplitude-integrated electroencephalogram (aEEG) recovery was more rapid for HT+IN huMSCs compared with HT from 25 h to 42 h and 49 h to 54 h (P ≤ 0.05). MRS phosphocreatine/inorganic phosphate was higher on day 2 in HT+IN huMSCs than HT (P = 0.035). Comparing HT+IN huMSCs with HT and HT+IV huMSCs, there were increased OLIG2 counts in hippocampus (P = 0.011 and 0.018, respectively), internal capsule (P = 0.013 and 0.037, respectively) and periventricular white matter (P = 0.15 for IN versus IV huMSCs). Reduced TUNEL-positive cells were seen in internal capsule with HT+IN huMSCs versus HT (P = 0.05). PKH-labeled huMSCs were detected in the brain 12 h after IN administration., Conclusions: After global HI, compared with HT alone, the authors saw beneficial effects of HT+IN huMSCs administered at 24 h and 48 h (30 × 10 6 cells/kg total dose) based on more rapid aEEG recovery, improved 31 P MRS brain energy metabolism and increased oligodendrocyte survival at 72 h., (Copyright © 2020 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Intra-arterial DSA has been traditionally used for confirmation of cure following gamma knife radiosurgery for AVMs. Our aim was to evaluate whether 4D arterial spin-labeling MRA and contrast-enhanced time-resolved MRA in combination can be an alternative to DSA for confirmation of AVM obliteration following gamma knife radiosurgery., Materials and Methods: In this prospective study, 30 patients undergoing DSA for confirmation of obliteration following gamma knife radiosurgery for AVMs (criterion standard) also underwent MRA, including arterial spin-labeling MRA and contrast-enhanced time-resolved MRA. One dataset was technically unsatisfactory, and the case was excluded. The DSA and MRA datasets of 29 patients were independently and blindly evaluated by 2 observers regarding the presence/absence of residual AVMs., Results: The mean time between gamma knife radiosurgery and follow-up DSA/MRA was 53 months (95% CI, 42-64 months; range, 22-168 months). MRA total scanning time was 9 minutes and 17 seconds. Residual AVMs were detected on DSA in 9 subjects (obliteration rate = 69%). All residual AVMs were detected on at least 1 MRA sequence. Arterial spin-labeling MRA and contrast-enhanced time-resolved MRA showed excellent specificity and positive predictive values individually (100%). However, their sensitivity and negative predictive values were suboptimal due to 1 false-negative with arterial spin-labeling MRA and 2 with contrast-enhanced time-resolved MRA (sensitivity = 88% and 77%, negative predictive values = 95% and 90%, respectively). Both sensitivity and negative predictive values increased to 100% if a composite assessment of both MRA sequences was performed. Diagnostic accuracy (receiver operating characteristic) and agreement (κ) are maximized using arterial spin-labeling MRA and contrast-enhanced time-resolved MRA in combination (area under receiver operating characteristic curve = 1, P  < .001; κ  =  1, P  < .001, respectively)., Conclusions: Combining arterial spin-labeling MRA with contrast-enhanced time-resolved MRA holds promise as an alternative to DSA for confirmation of obliteration following gamma knife radiosurgery for brain AVMs, having provided 100% sensitivity and specificity in the study. Their combined use also enables reliable characterization of residual lesions., (© 2021 by American Journal of Neuroradiology.)

Background: Posterior fossa abnormalities (PFAs) are commonly identified within routine screening and are a frequent indication for fetal magnetic resonance imaging (MRI). Although biometric measurements of the posterior fossa (PF) are established on fetal ultrasound and MRI, qualitative visual assessments are predominantly used to differentiate PFAs., Objectives: This systematic review aimed to assess 2-dimensional (2D) biometric measurements currently in use for assessing the PF on fetal MRI to delineate different PFAs., Methods: The protocol was registered (PROSPERO ID CRD42019142162). Eligible studies included T2-weighted MRI PF measurements in fetuses with and without PFAs, including measurements of the PF, or other brain areas relevant to PFAs., Results: 59 studies were included - 6859 fetuses had 62 2D PF and related measurements. These included linear, area and angular measurements, representing measures of PF size, cerebellum/vermis, brainstem, and supratentorial measurements. 11 measurements were used in 10 or more studies and at least 1200 fetuses. These dimensions were used to characterise normal for gestational age, diagnose a range of pathologies, and predict outcome., Conclusion: A selection of validated 2D biometric measurements of the PF on fetal MRI may be useful for identification of PFA in different clinical settings. Consistent use of these measures, both clinically and for research, is recommended., (© 2020 John Wiley & Sons, Ltd.)

Objective: We hypothesised that a multi-compartment magnetic resonance imaging (MRI) technique that is sensitive to fetal blood oxygenation would identify changes in placental blood volume and fetal blood oxygenation in pregnancies complicated by early-onset fetal growth restriction (FGR)., Design: Case-control study., Setting: London, UK., Population: Women with uncomplicated pregnancies (estimated fetal weight [EFW] >10th centile for gestational age [GA] and normal maternal and fetal Doppler ultrasound, n = 12) or early-onset FGR (EFW <3rd centile with or without abnormal Doppler ultrasound <32 weeks GA, n = 12) were studied., Methods: All women underwent MRI examination. Using a multi-compartment MRI technique, we quantified fetal and maternal blood volume and feto-placental blood oxygenation., Main Outcome Measures: Disease severity was stratified according to Doppler pulsatility index and the relationship to the MRI parameters was investigated, including the influence of GA at scan., Results: The FGR group (mean GA 27 +5  weeks, range 24 +2 to 33 +6  weeks) had a significantly lower EFW compared with the control group (mean GA 29 +1  weeks; -705 g, 95% CI -353 to -1057 g). MRI-derived feto-placental oxygen saturation was higher in controls compared with FGR (75 ± 9.6% versus 56 ± 16.2%, P = 0.02, 95% CI 7.8-30.3%). Feto-placental oxygen saturation estimation correlated strongly with GA at scan in controls (r = -0.83)., Conclusion: Using a novel multimodal MRI protocol we demonstrated reduced feto-placental blood oxygen saturation in pregnancies complicated by early-onset FGR. The degree of abnormality correlated with disease severity defined by ultrasound Doppler findings. Gestational age-dependent changes in oxygen saturation were also present in normal pregnancies., Tweetable Abstract: MRI reveals differences in feto-placental oxygen saturation between normal and FGR pregnancy that is associated with disease severity., (© 2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.)

As therapeutic hypothermia is only partially protective for neonatal encephalopathy, safe and effective adjunct therapies are urgently needed. Melatonin and erythropoietin show promise as safe and effective neuroprotective therapies. We hypothesized that melatonin and erythropoietin individually augment 12-h hypothermia ( double therapies) and hypothermia + melatonin + erythropoietin ( triple therapy ) leads to optimal brain protection. Following carotid artery occlusion and hypoxia, 49 male piglets (<48 h old) were randomized to: (i) hypothermia + vehicle ( n  = 12), (ii) hypothermia + melatonin (20 mg/kg over 2 h) ( n  = 12), (iii) hypothermia + erythropoietin (3000 U/kg bolus) ( n  = 13) or (iv) triple therapy ( n  = 12). Melatonin, erythropoietin or vehicle were given at 1, 24 and 48 h after hypoxia-ischaemia. Hypoxia-ischaemia severity was similar across groups. Therapeutic levels were achieved 3 hours after hypoxia-ischaemia for melatonin (15-30 mg/l) and within 30 min of erythropoietin administration (maximum concentration 10 000 mU/ml). Compared to hypothermia + vehicle, we observed faster amplitude-integrated EEG recovery from 25 to 30 h with hypothermia + melatonin ( P  = 0.02) and hypothermia + erythropoietin ( P  = 0.033) and from 55 to 60 h with triple therapy ( P  = 0.042). Magnetic resonance spectroscopy lactate/ N -acetyl aspartate peak ratio was lower at 66 h in hypothermia + melatonin ( P  = 0.012) and triple therapy ( P  = 0.032). With hypothermia + melatonin, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells were reduced in sensorimotor cortex ( P  = 0.017) and oligodendrocyte transcription factor 2 labelled-positive counts increased in hippocampus ( P  = 0.014) and periventricular white matter ( P  = 0.039). There was no reduction in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells with hypothermia + erythropoietin, but increased oligodendrocyte transcription factor 2 labelled-positive cells in 5 of 8 brain regions ( P  < 0.05). Overall, melatonin and erythropoietin were safe and effective adjunct therapies to hypothermia. Hypothermia + melatonin double therapy led to faster amplitude-integrated EEG recovery, amelioration of lactate/N-acetyl aspartate rise and reduction in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells in the sensorimotor cortex. Hypothermia + erythropoietin double therapy was in association with EEG recovery and was most effective in promoting oligodendrocyte survival. Triple therapy provided no added benefit over the double therapies in this 72-h study. Melatonin and erythropoietin influenced cell death and oligodendrocyte survival differently, reflecting distinct neuroprotective mechanisms which may become more visible with longer-term studies. Staggering the administration of therapies with early melatonin and later erythropoietin (after hypothermia) may provide better protection; each therapy has complementary actions which may be time critical during the neurotoxic cascade after hypoxia-ischaemia., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

BackgroundStenosis of the internal carotid artery has a higher risk for stroke. Many investigations have focused on structure and plaque composition as signs of plaque vulnerability, but few studies have analyzed hemodynamic changes in the brain as a risk factor.PurposeTo use 3-T MRI methods including contrast material-enhanced MR angiography, carotid plaque imaging, and arterial spin labeling (ASL) to identify imaging parameters that best help distinguish between asymptomatic and symptomatic participants with carotid stenosis.Materials and MethodsParticipants with carotid stenosis from two ongoing prospective studies who underwent ASL and carotid plaque imaging with use of 3-T MRI in the same setting from 2014 to 2018 were studied. Participants were assessed clinically for recent symptoms (transient ischemic attack or stroke) and divided equally into symptomatic and nonsymptomatic groups. Reviewers were blinded to the symptomatic status and MRI scans were analyzed for the degree of stenosis, plaque surface structure, presence of intraplaque hemorrhage (IPH), circle of Willis collaterals, and the presence and severity of arterial transit artifacts (ATAs) at ASL imaging. MRI findings were correlated with symptomatic status by using t tests and the Fisher exact test.ResultsA total of 44 participants (mean age, 71 years ± 10 [standard deviation]; 31 men) were evaluated. ATAs were seen only in participants with greater than 70% stenosis (16 of 28 patients; P < .001) and were associated with absence of anterior communicating artery (13 of 16 patients; P = .003). There was no association between history of symptoms and degree of stenosis (27 patients with ≥70% stenosis and 17 patients with <70%; P = .54), IPH (12 patients with IPH and 32 patients without IPH; P = .31), and plaque surface structure (17 patients with irregular or ulcerated plaque and 27 with smooth plaque; P = .54). Participants with ATAs ( n = 16) were more likely to be symptomatic than were those without ATAs ( n = 28) ( P = .004). Symptomatic status also was associated with the severity of ATAs ( P = .002).ConclusionArterial transit artifacts were the only factor associated with recent ischemic symptoms in participants with carotid stenosis. The degree of stenosis, plaque ulceration, and intraplaque hemorrhage were not associated with symptomatic status.© RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Zaharchuk in this issue.

Despite therapeutic hypothermia, survivors of neonatal encephalopathy have high rates of adverse outcome. Early surrogate outcome measures are needed to speed up the translation of neuroprotection trials. Thalamic lactate (Lac)/N-acetylaspartate (NAA) peak area ratio acquired with proton ( 1 H) magnetic resonance spectroscopy (MRS) accurately predicts 2-year neurodevelopmental outcome. We assessed the relationship between MR biomarkers acquired at 24-48 h following injury with cell death and neuroinflammation in a piglet model following various neuroprotective interventions. Sixty-seven piglets with hypoxia-ischemia, hypoxia alone, or lipopolysaccharide (LPS) sensitization were included, and neuroprotective interventions were therapeutic hypothermia, melatonin, and magnesium. MRS and diffusion-weighted imaging (DWI) were acquired at 24 and 48 h. At 48 h, experiments were terminated, and immunohistochemistry was assessed. There was a correlation between Lac/NAA and overall cell death [terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)] [mean Lac/NAA basal ganglia and thalamus (BGT) voxel r = 0.722, white matter (WM) voxel r = 0.784, p < 0.01] and microglial activation [ionized calcium-binding adapter molecule 1 (Iba1)] (BGT r = -0.786, WM r = -0.632, p < 0.01). Correlation with marker of caspase-dependent apoptosis [cleaved caspase 3 (CC3)] was lower (BGT r = -0.636, WM r = -0.495, p < 0.01). Relation between DWI and TUNEL was less robust (mean diffusivity BGT r = -0.615, fractional anisotropy BGT r = 0.523). Overall, Lac/NAA correlated best with cell death and microglial activation. These data align with clinical studies demonstrating Lac/NAA superiority as an outcome predictor in neonatal encephalopathy (NE) and support its use in preclinical and clinical neuroprotection studies., (Copyright © 2020 Pang, Martinello, Meehan, Avdic-Belltheus, Lingam, Sokolska, Mutshiya, Bainbridge, Golay and Robertson.)

Objective: Cerebrovascular diseases are one of the main global causes of death and disability in the adult population. The preferred imaging modality for the diagnostic routine is digital subtraction angiography, an invasive modality. Time-resolved three-dimensional arterial spin labeling magnetic resonance angiography (4D ASL MRA) is an alternative non-invasive modality, which captures morphological and blood flow data of the cerebrovascular system, with high spatial and temporal resolution. This work proposes advanced medical image processing methods that extract the anatomical and hemodynamic information contained in 4D ASL MRA datasets., Methods: A previously published segmentation method, which uses blood flow data to improve its accuracy, is extended to estimate blood flow parameters by fitting a mathematical model to the measured vascular signal. The estimated values are then refined using regression techniques within the cerebrovascular segmentation. The proposed method was evaluated using fifteen 4D ASL MRA phantoms, with ground-truth morphological and hemodynamic data, fifteen 4D ASL MRA datasets acquired from healthy volunteers, and two 4D ASL MRA datasets from patients with a stenosis., Results: The proposed method reached an average Dice similarity coefficient of 0.957 and 0.938 in the phantom and real dataset segmentation evaluations, respectively. The estimated blood flow parameter values are more similar to the ground-truth values after the refinement step, when using phantoms. A qualitative analysis showed that the refined blood flow estimation is more realistic compared to the raw hemodynamic parameters., Conclusion: The proposed method can provide accurate segmentations and blood flow parameter estimations in the cerebrovascular system using 4D ASL MRA datasets., Significance: The information obtained with the proposed method can help clinicians and researchers to study the cerebrovascular system non-invasively.

Purpose: Motion correction in placental DW-MRI is challenging due to maternal breathing motion, maternal movements, and rapid intensity changes. Parameter estimates are usually obtained using least-squares methods for voxel-wise fitting; however, they typically give noisy estimates due to low signal-to-noise ratio. We introduce a model-driven registration (MDR) technique which incorporates a placenta-specific signal model into the registration process, and we present a Bayesian approach for Diffusion-rElaxation Combined Imaging for Detailed placental Evaluation model to obtain individual and population trends in estimated parameters., Methods: MDR exploits the fact that a placenta signal model is available and thus we incorporate it into the registration to generate a series of target images. The proposed registration method is compared to a pre-existing method used for DCE-MRI data making use of principal components analysis. The Bayesian shrinkage prior (BSP) method has no user-defined parameters and therefore measures of parameter variation in a region of interest are determined by the data alone. The MDR method and the Bayesian approach were evaluated on 10 control 4D DW-MRI singleton placental data., Results: MDR method improves the alignment of placenta data compared to the pre-existing method. It also shows a further reduction of the residual error between the data and the fit. BSP approach showed higher precision leading to more clearly apparent spatial features in the parameter maps. Placental fetal oxygen saturation (FO 2 ) showed a negative linear correlation with gestational age., Conclusions: The proposed pipeline provides a robust framework for registering DW-MRI data and analyzing longitudinal changes of placental function., (© 2019 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

With the current practice of therapeutic hypothermia for neonatal encephalopathy, disability rates and the severity spectrum of cerebral palsy are reduced. Nevertheless, safe and effective adjunct therapies are needed to optimize outcomes. This study's objective was to assess if 18 mg/kg melatonin given rapidly over 2 h at 1 h after hypoxia-ischemia with cooling from 1-13 h was safe, achieved therapeutic levels within 3 h and augmented hypothermic neuroprotection. Following hypoxia-ischemia, 20 newborn piglets were randomized to: (i) Cooling 1-13 h (HT; n = 6); (ii) HT+ 2.5% ethanol vehicle (HT+V; n = 7); (iii) HT + Melatonin (HT+M; n = 7). Intensive care was maintained for 48 h; aEEG was acquired throughout, brain MRS acquired at 24 and 48 h and cell death (TUNEL) evaluated at 48 h. There were no differences for insult severity. Core temperature was higher in HT group for first hour after HI. Comparing HT+M to HT, aEEG scores recovered more quickly by 19 h (p < 0.05); comparing HT+V to HT, aEEG recovered from 31 h (p < 0.05). Brain phosphocreatine/inorganic phosphate and NTP/exchangeable phosphate were higher at 48 h in HT+M versus HT (p = 0.036, p = 0.049 respectively). Including both 24 h and 48 h measurements, the rise in Lactate/N-acetyl aspartate was reduced in white (p = 0.030) and grey matter (p = 0.038) after HI. Reduced overall TUNEL positive cells were observed in HT+M (47.1 cells/mm 2 ) compared to HT (123.8 cells/mm 2 ) (p = 0.0003) and HT+V (97.5 cells/mm 2 ) compared to HT (p = 0.012). Localized protection was seen in white matter for HT+M versus HT (p = 0.036) and internal capsule for HT+M compared to HT (p = 0.001) and HT+V versus HT (p = 0.006). Therapeutic melatonin levels (15-30mg/l) were achieved at 2 h and were neuroprotective following HI, but ethanol vehicle was partially protective.

There is a need for a method of real-time assessment of brain metabolism during neonatal hypoxic-ischaemic encephalopathy (HIE). We have used broadband near-infrared spectroscopy (NIRS) to monitor cerebral oxygenation and metabolic changes in 50 neonates with HIE undergoing therapeutic hypothermia treatment. In 24 neonates, 54 episodes of spontaneous decreases in peripheral oxygen saturation (desaturations) were recorded between 6 and 81 h after birth. We observed differences in the cerebral metabolic responses to these episodes that were related to the predicted outcome of the injury, as determined by subsequent magnetic resonance spectroscopy derived lactate/N-acetyl-aspartate. We demonstrated that a strong relationship between cerebral metabolism (broadband NIRS-measured cytochrome-c-oxidase (CCO)) and cerebral oxygenation was associated with unfavourable outcome; this is likely to be due to a lower cerebral metabolic rate and mitochondrial dysfunction in severe encephalopathy. Specifically, a decrease in the brain tissue oxidation state of CCO greater than 0.06 µM per 1 µM brain haemoglobin oxygenation drop was able to predict the outcome with 64% sensitivity and 79% specificity (receiver operating characteristic area under the curve = 0.73). With further work on the implementation of this methodology, broadband NIRS has the potential to provide an early, cotside, non-invasive, clinically relevant metabolic marker of perinatal hypoxic-ischaemic injury.

Brain arteriovenous malformations (AVMs) are congenital vascular anomalies characterized by arteriovenous shunting through a network of coiled and tortuous vessels. Because of this anatomy, the venous drainage of an AVM is hypothesized to contain more oxygenated, arterialized blood than healthy veins. By exploiting the paramagnetic properties of deoxygenated hemoglobin in venous blood using magnetic resonance imaging (MRI) quantitative susceptibility mapping (QSM), we aimed to explore venous density and oxygen saturation (SvO 2 ) in patients with a brain AVM. We considered three groups of subjects: patients with a brain AVM before treatment using gamma knife radiosurgery (GKR); patients three or more years post-GKR treatment; and healthy volunteers. First, we investigated the appearance of AVMs on QSM images. Then, we investigated whether QSM could detect increased SvO 2 in the veins draining the malformations. In patients before GKR, venous density, but not SvO 2 , was significantly larger in the hemisphere containing the AVM compared to the contralateral hemisphere (p = 0.03). Such asymmetry was not observed in patients after GKR or in healthy volunteers. Moreover, in all patients before GKR, the vein immediately draining the AVM nidus had a higher SvO 2 than healthy veins. Therefore, QSM can be used to detect SvO 2 alterations in brain AVMs. However, since factors such as flow-induced signal dephasing or the presence of hemosiderin deposits also strongly affect QSM image contrast, AVM vein segmentation must be performed based on alternative MRI acquisitions, e.g., time of flight magnetic resonance angiography or T 1 -weighted images. This is the first study to show, non-invasively, that AVM draining veins have a significantly larger SvO 2 than healthy veins, which is a finding congruent with arteriovenous shunting., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Cerebral blood flow (CBF) estimates from arterial spin labelling (ASL) show unexplained variability in older populations. We studied the impact of variation of haematocrit (Hct) on CBF estimates in a tri-ethnic elderly population., Materials and Methods: Approval for the study was obtained from the Fulham Research Ethics Committee and participants gave written informed consent. Pseudo-continuous arterial spin labelling was performed on 493 subjects (age 55-90) from a tri-ethnic community-based cohort recruited in London. CBF was estimated using a simplified Buxton equation, with and without correction for Hct measured from blood samples. Differences in perfusion were compared, stratified by sex, ethnicity and diabetes. Results of Student's t tests were reported with effect size., Results: Hct adjustment decreased CBF estimates in all categories except white European men. The decrease for women was 2.7 (3.0, 2.4) mL/100 g/min) (mean (95% confidence interval (CI)), p < 0.001 d = 0.38. The effect size differed by ethnicity with estimated mean perfusion in South Asian and African Caribbean women found to be lower by 3.0 (3.6, 2.5) mL/100 g/min, p < 0.001 d = 0.56 and 3.1 (3.6, 2.5) mL/100 g/min), p < 0.001 d = 0.48, respectively. Estimates of perfusion in subjects with diabetes decreased by 1.8 (2.3, 1.4) mL/100 g/min, p < 0.001 d = 0.23) following Hct correction. Correction for individual Hct altered sample frequency distributions of CBF values, especially in women of non-European ethnicity., Conclusion: ASL-derived CBF values in women, non-European ethnicities and individuals with diabetes are overestimated if calculations are not appropriately adjusted for individual Hct., Key Points: • CBF quantification from ASL using a fixed Hct of 43.5%, as recommended in the ISMRM white paper, may lead to erroneous CBF estimations particularly in non-European and female subjects. • Individually measured Hct values improve the accuracy of CBF estimation and, if these are not available, an adjusted value according to gender, ethnicity or diabetes status should be considered. • Hct-corrected ASL could be potentially important for CBF threshold decision making in the fields of neurodegenerative disease and neuro-oncology.

Objective: Brain proton ( 1 H) magnetic resonance spectroscopy (MRS) lactate/N-acetylaspartate (Lac/NAA) peak area ratio is used for prognostication in neonatal encephalopathy (NE). At 3 Tesla in NE babies, the objectives were to assess: (1) sensitivity and specificity of basal ganglia and thalamus (BGT) 1 H MRS Lac/NAA for the prediction of Bayley III outcomes at 2 years using optimised metabolite fitting (Tarquin) with threonine and total NAA; (2) prediction of motor outcome with diffusion-weighted MRI; (3) BGT Lac/NAA correlation with the National Institute of Child Health and Human Development (NICHD) MRI score., Subjects and Methods: 55 (16 inborn, 39 outborn) infants at 39w+5 d (35w+5d-42w+0d) with NE admitted between February 2012 and August 2014 to University College London Hospitals for therapeutic hypothermia underwent MRI and 1 H MRS at 3T on day 2-14 (median day 5). MRIs were scored. Bayley III was assessed at 24 (22-26) months., Results: 16 babies died (1 inborn, 15 outborn); 20, 19 and 21 babies had poor motor, cognitive and language outcomes. Using a threshold of 0.39, sensitivity and specificity of BGT Lac/NAA for 2-year motor outcome was 100% and 97%, cognition 90% and 97% and language 81% and 97%, respectively. Sensitivity and specificity for motor outcome of mean diffusivity (threshold 0.001 mm 2 /s) up to day 9 was 72% and 100% and fractional anisotropy (threshold 0.198) was 39% and 94%, respectively. Lac/NAA correlated with BGT injury on NICHD scores (2A, 2B, 3)., Conclusion: BGT Lac/NAA on 1 H MRS at 3T within 14 days accurately predicts 2-year motor, cognitive and language outcome and may be a marker directing decisions for therapies after cooling., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To determine the diagnostic accuracy and interobserver concordance of whole-body (WB)-MRI, vs. 99m Tc bone scintigraphy (BS) and 18 fluoro-ethyl-choline ( 18 F-choline) PET/CT for the primary staging of intermediate/high-risk prostate cancer., Methods: An institutional review board approved prospective cohort study carried out between July 2012 and November 2015, whereby 56 men prospectively underwent 3.0-T multiparametric (mp)-WB-MRI in addition to BS (all patients) ± 18 F-choline PET/CT (33 patients). MRI comprised pre- and post-contrast modified Dixon (mDixon), T2-weighted (T2W) imaging, and diffusion-weighted imaging (DWI). Patients underwent follow-up mp-WB-MRI at 1 year to derive the reference standard. WB-MRIs were reviewed by two radiologists applying a 6-point scale and a locked sequential read (LSR) paradigm for the suspicion of nodal (N) and metastatic disease (M1a and M1b)., Results: The mean sensitivity/specificity of WB-MRI for N1 disease was 1.00/0.96 respectively, compared with 1.00/0.82 for 18 F-choline PET/CT. The mean sensitivity and specificity of WB-MRI, 18 F-choline PET/CT, and BS were 0.90/0.88, 0.80/0.92, and 0.60/1.00 for M1b disease. ROC-AUC did not show statistically significant improvement for each component of the LSR; mean ROC-AUC 0.92, 0.94, and 0.93 (p < 0.05) for mDixon + DWI, + T2WI, and + contrast respectively. WB-MRI had an interobserver concordance (κ) of 0.79, 0.68, and 0.58 for N1, M1a, and M1b diseases respectively., Conclusions: WB-MRI provides high levels of diagnostic accuracy for both nodal and metastatic bone disease, with higher levels of sensitivity than BS for metastatic disease, and similar performance to 18 F-choline PET/CT. T2 and post-contrast mDixon had no significant additive value above a protocol comprising mDixon and DWI alone., Key Points: • A whole-body MRI protocol comprising unenhanced mDixon and diffusion-weighted imaging provides high levels of diagnostic accuracy for the primary staging of intermediate- and high-risk prostate cancer. • The diagnostic accuracy of whole-body MRI is much higher than that of bone scintigraphy, as currently recommended for clinical use. • Staging using WB-MRI, rather than bone scintigraphy, could result in better patient stratification and treatment delivery than is currently provided to patients worldwide.

Pseudo-continuous arterial spin labelling (pCASL) is the MRI method of choice for non-invasive perfusion measurement in research and clinical practice. Knowledge of the labelling efficiency, α, is essential for accurate quantification of cerebral blood flow (CBF). Typically, a theoretical α value is used, based on an idealistic model and an assumption of spins flowing perpendicularly to the labelling plane. The aim of this work was to investigate the effect of violating this assumption, and to characterize the influence of labelling plane angulation with respect to the vessel direction on labelling efficiency and measured CBF. The effect of labelling plane angulation on labelling efficiency was demonstrated using a numerical simulation of spins at different velocities. Acquisitions from healthy volunteers were used to test the effect of a range of angulation offsets. Additional sub-optimal positions of the labelling plane with respect to the vertebral arteries, at locations where the direction of flow changes significantly from the head-foot direction, were also considered. No significant change in the measured CBF was seen when the labelling plane was angled up to 60° to the labelled vessel or when it was placed in sub-optimal positions. This study shows that in adult subjects, the efficiency of pCASL is robust to the angulation and positioning of the labelling plane beyond the range of potential operator error., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We assessed whether HIV status was associated with white matter hyperintensities (WMH), a neuroimaging correlate of cerebral small vessel disease (CSVD), in men aged ≥50 years. A cross-sectional substudy was nested within a larger cohort study. Virologically suppressed men living with HIV (MLWH) and demographically matched HIV-negative men aged ≥50 underwent magnetic resonance imaging (MRI) at 3 Tesla. Sequences included volumetric three-dimensional (3D) T1-weighted, fluid-attenuated inversion recovery and pseudocontinuous arterial spin labeling. Regional segmentation by automated image processing algorithms was used to extract WMH volume (WMHV) and resting cerebral blood flow (CBF). The association between HIV status and WMHV as a proportion of intracranial volume (ICV; log-transformed) was estimated using a multivariable linear regression model. Thirty-eight MLWH [median age 59 years (interquartile range, IQR 55-64)] and 37 HIV-negative [median 58 years (54-63)] men were analyzed. MLWH had median CD4 + count 570 (470-700) cells/μL and a median time since diagnosis of 20 (14-24) years. Framingham 10-year risk of cardiovascular disease was 6.5% in MLWH and 7.4% in controls. Two (5%) MLWH reported a history of stroke or transient ischemic attack and five (13%) reported coronary heart disease compared with none of the controls. The total WMHV in MLWH was 1,696 μL (IQR 1,229-3,268 μL) or 0.10% of ICV compared with 1,627 μL (IQR 1,032-3,077 μL), also 0.10% of ICV in the HIV-negative group ( p  = .43). In the multivariable model, WMHV/ICV was not associated with HIV status ( p  = .86). There was an age-dependent decline in cortical CBF [-3.9 mL/100 mL/min per decade of life (95% confidence interval 1.1-6.7 mL)] but no association between CBF and HIV status ( p  > .2 in all brain regions analyzed). In conclusion, we found no quantitative MRI evidence of an increased burden of CSVD in MLWH aged 50 years and older.

Background: Protease inhibitor monotherapy (PIM) for human immunodeficiency virus (HIV) may exert suboptimal viral control in the central nervous system. We determined whether cerebral blood flow (CBF) and regional brain volumes were associated with PIM, and whether specific cognitive domains were associated with imaging biomarkers., Methods: Cognitive assessments and brain magnetic resonance imaging were performed after the final visit of a randomized HIV-treatment strategy trial. Participants were virologically suppressed on triple therapy at trial entry and followed for 3-5 years. We studied 37 patients randomized to ongoing triple therapy and 39 randomized to PIM. Resting CBF and normalized volumes were calculated for brain regions of interest, and correlated with treatment strategy and neuropsychological performance., Results: Mean age was 48.1 years (standard deviation 8.6 years), 63 male (83%), and 64 white (84%). Participants had median 8.1 years (interquartile range 6.4, 10.8) of antiretroviral therapy experience and CD4+ counts of median 640 cells/mm3 (interquartile range 490, 780). We found no difference between treatment arms in CBF or regional volumes. Regardless of treatment arm, poorer fine motor performance correlated with lower CBF in the caudate nucleus (P = .01), thalamus (P = .04), frontal cortex (P = .01), occipital cortex (P = .004), and cingulate cortex (P = .02), and was associated with smaller supratentorial white matter volume (decrease of 0.16 in Z-score per -1% of intracranial volume, 95% confidence interval 0.02-0.29; P = .023)., Conclusions: PIM does not confer an additional risk of neurological injury compared with triple therapy. There were correlations between fine motor impairment, grey matter hypoperfusion, and white matter volume loss., Clinical Trials Registration: ISRCTN-04857074., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Purpose: The placenta is a vital organ for the exchange of oxygen, nutrients, and waste products between fetus and mother. The placenta may suffer from several pathologies, which affect this fetal-maternal exchange, thus the flow properties of the placenta are of interest in determining the course of pregnancy. In this work, we propose a new multiparametric model for placental tissue signal in MRI., Methods: We describe a method that separates fetal and maternal flow characteristics of the placenta using a 3-compartment model comprising fast and slowly circulating fluid pools, and a tissue pool is fitted to overlapping multiecho T2 relaxometry and diffusion MRI with low b-values. We implemented the combined model and acquisition on a standard 1.5 Tesla clinical system with acquisition taking less than 20 minutes., Results: We apply this combined acquisition in 6 control singleton placentas. Mean myometrial T2 relaxation time was 123.63 (±6.71) ms. Mean T2 relaxation time of maternal blood was 202.17 (±92.98) ms. In the placenta, mean T2 relaxation time of the fetal blood component was 144.89 (±54.42) ms. Mean ratio of maternal to fetal blood volume was 1.16 (±0.6), and mean fetal blood saturation was 72.93 (±20.11)% across all 6 cases., Conclusion: The novel acquisition in this work allows the measurement of histologically relevant physical parameters, such as the relative proportions of vascular spaces. In the placenta, this may help us to better understand the physiological properties of the tissue in disease., (© 2018 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Therapeutic hypothermia is only partially protective for neonatal encephalopathy; there is an urgent need to develop treatments that augment cooling. Our objective was to assess safety, efficacy and pharmacokinetics of 5 and 15 mg/kg/24 h melatonin (proprietary formulation) administered at 2 h and 26 h after hypoxia-ischemia (HI) with cooling in a piglet model. Following moderate cerebral HI, 30 piglets were eligible and randomized to: i) Hypothermia (33.5 °C, 2-26 h) and vehicle (HT + V;n = 13); b) HT and 5 mg/kg melatonin over 6 h at 2 h and 26 h after HI (HT + Mel-5;n = 4); c) HT and 15 mg/kg melatonin over 6 h at 2 h and 26 h after HI (HT + Mel-15;n = 13). Intensive care was maintained for 48 h; brain MRS was acquired and cell death (TUNEL) evaluated at 48 h. Comparing HT + V with HT + Mel-5 and HT + Mel-15, there was no difference in blood pressure or inotropic support needed, brain Lactate/N Acetylaspartate at 24 h and 48 h was similar, ATP/phosphate pool was higher for HT + Mel-15 versus HT + V at 24 h (p = 0.038) but not 48 h. A localized reduction in TUNEL positive cell death was observed in the sensorimotor cortex in the 15 mg/kg melatonin group (HT + Mel-15 versus HT + V; p < 0.003) but not in the 5 mg/kg melatonin group (HT + Mel-5 versus HT + V; p = 0.808). Putative therapeutic melatonin levels were reached 8 h after HI (10 4 increase from baseline; ~15-30 mg/l). Mean ± SD peak plasma melatonin levels after the first infusion were 0.0014 ± 0.0012 mg/l in the HT + V group, 3.97 ± 1.53 mg/l in the HT + Mel-5 group and 16.8 ± 8.3 mg/l in the HT + Mel-15 group. Protection was dose dependent; 15 mg/kg melatonin started 2 h after HI, given over 6 h, was well tolerated and augmented hypothermic protection in sensorimotor cortex. Earlier attainment of therapeutic plasma melatonin levels may optimize protection by targeting initial events of reperfusion injury. The time window for intervention with melatonin, as adjunct therapy with cooling, is likely to be narrow and should be considered in designing future clinical studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Hypoxic ischemic encephalopathy (HIE) leads to significant morbidity and mortality. Impaired autoregulation after hypoxia-ischaemia has been suggested to contribute further to injury. Thalamic lactate/N-Acetylasperate (Lac/NAA) peak area ratio of > 0.3 on proton ( 1 H) magnetic resonance spectroscopy (MRS) is associated with poor neurodevelopment outcome following HIE. Cytochrome-c-oxidase (CCO) plays a central role in mitochondrial oxidative metabolism and ATP synthesis. Using a novel broadband NIRS system, we investigated the impact of pressure passivity of cerebral metabolism (CCO), oxygenation (haemoglobin difference (HbD)) and cerebral blood volume (total haemoglobin (HbT)) in 23 term infants following HIE during therapeutic hypothermia (HT). Sixty-minute epochs of data from each infant were studied using wavelet analysis at a mean age of 48 h. Wavelet semblance (a measure of phase difference) was calculated to compare reactivity between mean arterial blood pressure (MABP) with oxCCO, HbD and HbT. OxCCO-MABP semblance correlated with thalamic Lac/NAA ( r = 0.48, p = 0.02). OxCCO-MABP semblance also differed between groups of infants with mild to moderate and severe injury measured using brain MRI score ( p = 0.04), thalamic Lac/NAA ( p = 0.04) and neurodevelopmental outcome at one year ( p = 0.04). Pressure passive changes in cerebral metabolism were associated with injury severity indicated by thalamic Lac/NAA, MRI scores and neurodevelopmental assessment at one year of age.

Introduction: Lower cerebral blood flow (CBF) is associated with cardiovascular disease and vascular risk factors, and is increasingly acknowledged as an important contributor to cognitive decline and dementia. In this cross-sectional study, we examined the association between CBF and cognitive functioning in a community-based, multi-ethnic cohort. Methods: From the SABRE (Southall and Brent Revisited) study, we included 214 European, 151 South Asian and 87 African Caribbean participants (71 ± 5 years; 39%F). We used 3T pseudo-continuous arterial spin labeling to estimate whole-brain, hematocrit corrected CBF. We measured global cognition and three cognitive domains (memory, executive functioning/attention and language) with a neuropsychological test battery. Associations were investigated using linear regression analyses, adjusted for demographic variables, vascular risk factors and MRI measures. Results: Across groups, we found an association between higher CBF and better performance on executive functioning/attention (standardized ß [stß] = 0.11, p < 0.05). Stratification for ethnicity showed associations between higher CBF and better performance on memory and executive functioning/attention in the white European group (stß = 0.14; p < 0.05 and stß = 0.18; p < 0.01 respectively), associations were weaker in the South Asian and African Caribbean groups. Conclusions: In a multi-ethnic community-based cohort we showed modest associations between CBF and cognitive functioning. In particular, we found an association between higher CBF and better performance on executive functioning/attention and memory in the white European group. The observations are consistent with the proposed role of cerebral hemodynamics in cognitive decline.

Objectives: To evaluate whole-body MRI (WB-MRI) parameters significantly associated with treatment response in multiple myeloma (MM)., Methods: Twenty-one MM patients underwent WB-MRI at diagnosis and after two cycles of chemotherapy. Scans acquired at 3.0 T included T2, diffusion-weighted-imaging (DWI) and mDixon pre- and post-contrast. Twenty focal lesions (FLs) matched on DWI and post-contrast mDixon were selected for each time point. Estimated tumour volume (eTV), apparent diffusion coefficient (ADC), enhancement ratio (ER) and signal fat fraction (sFF) were derived. Clinical treatment response to chemotherapy was assessed using conventional criteria. Significance of temporal parameter change was assessed by the paired t test and receiver operating characteristics/area under the curve (AUC) analysis was performed. Parameter repeatability was assessed by interclass correlation (ICC) and Bland-Altman analysis of 10 healthy volunteers scanned at two time points., Results: Fifteen of 21 patients responded to treatment. Of 254 FLs analysed, sFF (p < 0.0001) and ADC (p = 0.001) significantly increased in responders but not non-responders. eTV significantly decreased in 19/21 cases. Focal lesion sFF was the best discriminator of treatment response (AUC 1.0). Bone sFF repeatability was excellent (ICC 0.98) and better than bone ADC (ICC 0.47)., Conclusion: WB-MRI derived focal lesion sFF shows promise as an imaging biomarker of treatment response in newly diagnosed MM., Key Points: • Bone signal fat fraction using mDixon is a robust quantifiable parameter • Fat fraction and ADC significantly increase in myeloma lesions responding to treatment • Bone lesion fat fraction is the best discriminator of myeloma treatment response.

Cross-sectional imaging techniques are being increasingly used for disease evaluation in patients with multiple myeloma. Whole body magnetic resonance imaging (WB-MRI) scanning is superior to plain radiography in baseline assessment of patients but changes following treatment have not been systematically explored. We carried out paired WB-MRI scans in 21 newly diagnosed patients prior to, and 8-weeks after, starting chemotherapy, and analysed stringently selected focal lesions (FLs) for parametric changes. A total of 323 FLs were evaluated, median 20 per patient. At 8 weeks, there was a reduction in estimated tumour volume (eTV), and an increase in signal fat fraction (sFF) and apparent diffusion coefficient (ADC) in the group as a whole (P < 0·001). Patients who achieved complete/very good partial response (CR/VGPR) to induction had a significantly greater increase in sFF compared to those achieving ≤ partial response (PR; P = 0·001). When analysed on a per-patient basis, all patients achieving CR/VGPR had a significant sFF increase in their FL's, in contrast to patients achieving ≤PR. sFF changes in patients reaching maximal response within 100 days (fast responders) were greater compared to slow responders (P = 0·001). Receiver Operator Characteristic analysis indicated that sFF changes at 8 weeks were the best biomarker (area under the Curve 0·95) for an inferior response (≤PR). We conclude that early lesional sFF changes may provide important information on depth of response, and are worthy of further prospective study., (© 2016 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.)