Magdalena Sokolska

Brain Perfusion Imaging in Neonates: An Overview.

SUMMARY: The development of cognitive function in children has been related to a regional metabolic increase and an increase in regional brain perfusion. Moreover, brain perfusion plays an important role in the pathogenesis of brain damage in high-risk neonates, both preterm and full-term asphyxiated infants. In this article, we will review and discuss several existing imaging techniques for assessing neonatal brain perfusion.

Whole body magnetic resonance imaging in newly diagnosed multiple myeloma: early changes in lesional signal fat fraction predict disease 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 FLs, 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.

Pressure passivity of cerebral mitochondrial metabolism is associated with poor outcome following perinatal hypoxic ischemic brain injury

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 (1H) 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.

Melatonin as an adjunct to therapeutic hypothermia in a piglet model of neonatal encephalopathy: A translational study

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 (104 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.

Separating fetal and maternal placenta circulations using multiparametric MRI: Separating placenta circulations using multiparametric MRI

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.

Cerebral Blood Flow and Cognitive Functioning in a Community-Based, Multi-Ethnic Cohort: The SABRE Study

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.

Brain Perfusion, Regional Volumes, and Cognitive Function in Human Immunodeficiency Virus–positive Patients Treated With Protease Inhibitor Monotherapy

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.

Proton magnetic resonance spectroscopy lactate/N-acetylaspartate within 2 weeks of birth accurately predicts 2-year motor, cognitive and language outcomes in neonatal encephalopathy after therapeutic hypothermia

Objective Brain proton (1H) 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) 1H 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 1H 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 mm2/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 1H 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.

PROTOCOL HARMONISATION AND IN-VIVO COMPARISON OF ARTERIAL SPIN LABELLING PERFUSION MRI FOR MULTICENTER CLINICAL TRIALS

temporal lobe and parietal lobe may occur prior to those in the hippocampus and entorhinal cortex (Insel et al., 2015). This suggests that the accepted event sequence may need to be revised using better biomarkers of regional atrophy. Methods: We used CSF and structural MRI data from the Alzheimer’s Disease Neuroimaging (ADNI) dataset, restricting our analysis to 732 images from 204 APOE+ (at least one APOE4 allele) subjects: 22 healthy, 120 MCI and 62 Alzheimer’s subjects. We used a recently developed parametric Bayesian multi-task learning based longitudinal trajectory model, applying it to model twenty cortical ROI volumes parcellated via GIF (Cardoso et al., 2015). The model robustly estimates intercepts and slopes for each subject by sharing information across subjects. We used the slope estimates from these models as biomarkers of regional brain atrophy and built an event-based model (EBM) as in Young et al., (2014), which included CSF measures and brain structure measures at baseline. To reduce the number of biomarkers, we selected the regional slope and baseline biomarkers that had a minimum eta-squared effect size of 0.2 between healthy and Alzheimer’s disease groups. We compared our results to an event-based model built using ordinary least squares (OLS) based estimates of regional rates of change. Results: The top EBM in Figure 1, which uses OLS slopes, is in close agreement with Young et al., (2014). The bottom EBM, which uses multi-task learning based slopes, shows abnormalities within the temporal, parietal, frontal and insula occurring alongside changes in CSF phosphorylated and total tau. Conclusions:Changes in regional volumes may co-occur with changes in CSF proteins, predating changes within the medial-temporal lobe. References: Cardoso, M.J., et al. 2015. IEEE TMI Insel, P.S., et al., 2015. Alzheimers Dementia Jack, C.R., et al., 2010. Lancet Neurology Young, A.L., et al. 2014. Brain.

OP05.08: Novel placental evaluation using multimodal MRI

Results: The coefficients of variation in mature fetuses were greater than 30% for placentas in-vivo, greater than 35 for placentas in-vitro, greater than 29% for liver tissue and greater than 33% for lung tissue. In mature fetuses strain index (SI) for fetal lung was greater than 0,9, for placentas in vivo greater than 1,0, for placentas in vitro, greater than 1,5, for liver tissue greater than 0,7. We found significant difference in SI in normal pregnancies comparing with pre-eclamptic pregnancies and diabetic pregnancies. We did not find significant difference between lung volumes in all investigated patients. Conclusions: The coefficient of variation values and strain stiffness for placentas in vivo and in vitro, and fetal lungs and liver increase during pregnancy in normal and pre-eclamptic patients with increasing gestational age and decrease in diabetic patients. Lung volumes increase during pregnancy in normal, pre-eclamptic and diabetic patients.