How well does neonatal neuroimaging correlate with neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy?

BACKGROUND: In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear. METHODS: Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4-6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years. RESULTS: Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5-5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury. CONCLUSION: In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes. IMPACT: Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes

Integrating neuroimaging biomarkers into the multicentre, high-dose erythropoietin for asphyxia and encephalopathy (HEAL) trial: rationale, protocol and harmonisation

Introduction: MRI and MR spectroscopy (MRS) provide early biomarkers of brain injury and treatment response in neonates with hypoxic-ischaemic encephalopathy). Still, there are challenges to incorporating neuroimaging biomarkers into multisite randomised controlled trials. In this paper, we provide the rationale for incorporating MRI and MRS biomarkers into the multisite, phase III high-dose erythropoietin for asphyxia and encephalopathy (HEAL) Trial, the MRI/S protocol and describe the strategies used for harmonisation across multiple MRI platforms. Methods and analysis: Neonates with moderate or severe encephalopathy enrolled in the multisite HEAL trial undergo MRI and MRS between 96 and 144 hours of age using standardised neuroimaging protocols. MRI and MRS data are processed centrally and used to determine a brain injury score and quantitative measures of lactate and n-acetylaspartate. Harmonisation is achieved through standardisation-thereby reducing intrasite and intersite variance, real-time quality assurance monitoring and phantom scans. Ethics and dissemination: IRB approval was obtained at each participating site and written consent obtained from parents prior to participation in HEAL. Additional oversight is provided by an National Institutes of Health-appointed data safety monitoring board and medical monitor

Citrate Concentrations Increase with Hypoperfusion in Pediatric Diffuse Intrinsic Pontine Glioma

Citrate, a tricarboxylic acid cycle intermediate, is present in high concentrations in pediatric diffuse intrinsic pontine gliomas (DIPG). Since citrate increases during hypoxia in animal studies, we hypothesized that it accumulates in DIPG when hypoperfused. Relative tumor blood volumes (rTBV) were determined, using dynamic susceptibility contrast-enhanced magnetic resonance imaging, in twelve children [median age 8.2 (range 3.2-14.5) years] with DIPG and compared to citrate concentrations measured with in vivo proton magnetic resonance spectroscopy ((1)H MRS). Tissue perfusion and metabolite concentration were assessed at initial presentation and over the clinical course, yielding 36 and 46 perfusion and MR spectroscopy datasets, respectively. At presentation, DIPG blood volume was 60 ± 27 % of that measured for normal cerebellum. Citrate, which is not detectable in normal brain tissue, was present in DIPG at concentrations of 3.81 ± 1.44 mmol/kg tissue. Over the course of the disease and treatment, rTBV increased and citrate decreased (both p \u3c 0.05) with an inverse correlation (p = 0.028). Citrate accumulation is associated with tissue hypoperfusion in DIPG

Citrate Concentrations Increase with Hypoperfusion in Pediatric Diffuse Intrinsic Pontine Glioma

Citrate, a tricarboxylic acid cycle intermediate, is present in high concentrations in pediatric diffuse intrinsic pontine gliomas (DIPG). Since citrate increases during hypoxia in animal studies, we hypothesized that it accumulates in DIPG when hypoperfused. Relative tumor blood volumes (rTBV) were determined, using dynamic susceptibility contrast-enhanced magnetic resonance imaging, in twelve children [median age 8.2 (range 3.2-14.5) years] with DIPG and compared to citrate concentrations measured with in vivo proton magnetic resonance spectroscopy ((1)H MRS). Tissue perfusion and metabolite concentration were assessed at initial presentation and over the clinical course, yielding 36 and 46 perfusion and MR spectroscopy datasets, respectively. At presentation, DIPG blood volume was 60 ± 27 % of that measured for normal cerebellum. Citrate, which is not detectable in normal brain tissue, was present in DIPG at concentrations of 3.81 ± 1.44 mmol/kg tissue. Over the course of the disease and treatment, rTBV increased and citrate decreased (both p \u3c 0.05) with an inverse correlation (p = 0.028). Citrate accumulation is associated with tissue hypoperfusion in DIPG

Parametric Mapping of Oxygen Activity in Human Placenta across Gestation using in utero BOLD imaging

International audienceSynopsis We present here, for the rst time, parametric maps of oxygen activity in normal human placenta using in utero functional MR imaging. Our method highlights anatomical and gestational age dependent patterns in placental activity. These maps can be used to gain insight into normative placental function and identifying insuucient or abnormal placental functioning at various points in gestation. Introduction Our current understanding of placental development and function is based on animal imaging and ex-vivo studies of placenta obtained after delivery or interrupted pregnancies. Previous human imaging studies were restricted to understanding hyperoxygentation or adverse developmental conditions such as fetal growth restriction (FGR), placental previa, placenta accrete, etc.. These studies strongly indicate that improved in-vivo delineation of vasculogenesis and angiogenesis of the placenta has the potential to provide better insight into the pathogenesis of placental dysfunction. By leveraging non-invasive, high-resolution imaging capabilities of in utero fetal MRI, we present a spatiotemporal analysis of normative fetoplacental oxygenation patterns at various time points in gestation. We hypothesize that (a) spatial variance of BOLD placental signal would age-dependent , and (b) that serial parametric maps of BOLD signal would reveal important anatomic insights about the feto-placental and maternal circulation. Methods We conducted a prospective two-site study of placental development in which 20 maternal subjects with normal pregnancies were recruited between 26-37 gestational weeks (GW). Images were acquired using 3T Philips Ingenia or Siemens Skyra machines. Over a 5-10 minute total acquisition time, BOLD images (1.5 mm x 1.5 mm x 4 mm) were acquired using an EPI sequence in blocks of 60 images with TR/TE = 3000/35 ms, ip angle = 90°. In addition, a high resolution T2 weighted images (1 mm x 1 mm x 3 mm) were acquired using a 3D FFE sequence (TR/TE = 3.1/1.6 ms, ip angle = 75°). BOLD images were processed using the "Functional MRI of the Brain" Software Library (FSL). The BOLD signal was motion corrected, co registered to the T2 images and ltered to remove physiological noise such as cardiac, breathing and metabolic uctuations. An F test was used to test the relationship between spatial signal variations and gestational age. To compare oxygenation levels within the placenta, we computed the normalized BOLD values after averaging the amplitude of the BOLD signal over the duration of the study for each time point. Results We found that the spatial variance of the BOLD signal was age dependent (F= 2.25, p<0.001). We then generated parametric maps of oxygen activity in a subset of fetuses at various gestational ages. Figure 1 shows the mean BOLD signal values across the placenta between 26 and 36 GW. The parametric mapping delineates two distinct regions of high oxygenation activity, corresponding to the fetal side (adjacent to the site of umbilical cord attachment) and the maternal side (along the uterine wall). The regions of high activity also occurred in speciic clusters. The size and number if these high-activity regions increased from 26 to 28 GW. We then observed a drop in the number and size of these regions at 29 GW with a further decrease at 36 GW. Discussion Our results clearly indicate that oxygenation is spatially heterogenous across the placenta with oxygen activity concentrated at speciic anatomical locations. The spatial variance in oxygen activity is also age-dependent. The reduction in size and number of high activity clusters at 29 GW and beyond correlates with the involution of the placenta in the third trimester leading to birth. Lower BOLD signal values in the middle of the placenta could correspond to the lack of deoxyhemoglobin as these regions only transport oxygen to the umbilical cord. The oxygenation maps provide a baseline for how oxygen activity occurs and changes over gestation giving us a better understanding of fetoplacental haemodynamics and placental transfer. They may also be used to identify abnormal oxygenation patterns in a placenta thereby acting as a marker for early detection of FGR or insuucient placental function. Conclusion There are age-dependent, spatial variances of BOLD signal in the placenta which may correlate with angiogenesis. Using parametric mapping of placental BOLD signal, we have demonstrated that placental oxygenation activity is concentrated at speciic anatomical locations associated with feto-maternal oxygen exchange. The non-invasive and repeatable methods presented here may facilitate better predictions of placental dysfunction in high-risk pregnancies and inform perinatal care

Magnetic Resonance Spectroscopy Metabolites as Biomarkers of Disease Status in Pediatric Diffuse Intrinsic Pontine Gliomas (DIPG) Treated with Glioma-Associated Antigen Peptide Vaccines

Purpose: Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive tumors with no currently available curative therapy. This study evaluated whether measurements of in vivo cell metabolites using magnetic resonance spectroscopy (MRS) may serve as biomarkers of response to therapy, including progression. Methods: Single-voxel MR spectra were serially acquired in two cohorts of patients with DIPG treated with radiation therapy (RT) with or without concurrent chemotherapy and prior to progression: 14 participants were enrolled in a clinical trial of adjuvant glioma-associated antigen peptide vaccines and 32 patients were enrolled who did not receive adjuvant vaccine therapy. Spearman correlations measured overall survival associations with absolute metabolite concentrations of myo-inositol (mI), creatine (Cr), and n-acetyl-aspartate (NAA) and their ratios relative to choline (Cho) during three specified time periods following completion of RT. Linear mixed-effects regression models evaluated the longitudinal associations between metabolite ratios and time from death (terminal decline). Results: Overall survival was not associated with metabolite ratios obtained shortly after RT (1.9&ndash;3.8 months post-diagnosis) in either cohort. In the vaccine cohort, an elevated mI/Cho ratio after 2&ndash;3 doses (3.9&ndash;5.2 months post-diagnosis) was associated with longer survival (rho = 0.92, 95% CI 0.67&ndash;0.98). Scans performed up to 6 months before death showed a terminal decline in the mI/Cho ratio, with an average of 0.37 ratio/month in vaccine patients (95% CI 0.11&ndash;0.63) and 0.26 (0.04&ndash;0.48) in the non-vaccine cohort. Conclusion: Higher mI/Cho ratios following RT, consistent with less proliferate tumors and decreased cell turnover, were associated with longer survival, suggesting that this ratio can serve as a biomarker of prognosis following RT. This finding was seen in both cohorts, although the association with OS was detected earlier in the vaccine cohort. Increased mI/Cho (possibly reflecting immune-effector cell influx into the tumor as a mechanism of tumor response) requires further study

The Impact of Venoarterial and Venovenous Extracorporeal Membrane Oxygenation on Cerebral Metabolism in the Newborn Brain.

Extracorporeal membrane oxygenation (ECMO) is an effective therapy for supporting infants with reversible cardiopulmonary failure. Still, survivors are at risk for long-term neurodevelopmental impairments, the cause of which is not fully understood.To elucidate the effects of ECMO on the newborn brain. We hypothesized that the cerebral metabolic profile of neonates who received ECMO would differ from neonates who did not receive ECMO. To address this, we used magnetic resonance spectroscopy (1H-MRS) to investigate the effects of venoarterial and venovenous ECMO on cerebral metabolism.41 neonates treated with ECMO were contrasted to 38 age-matched neonates.All 1H-MRS data were acquired from standardized grey matter and white matter regions of interest using a short-echo (TE = 35 milliseconds), point-resolved spectroscopy sequence (PRESS) and quantitated using LCModel. Metabolite concentrations (mmol/kg) were compared across groups using multivariate analysis of covariance. Elevated creatine (p = 0.002) and choline (p = 0.005) concentrations were observed in the grey matter among neonates treated with ECMO relative to the reference group. Likewise, choline concentrations were elevated in the white matter (p = 0.003) while glutamate was reduced (p = 0.03). Contrasts between ECMO groups revealed lower osmolite concentrations (e.g. myoinositol) among the venovenous ECMO group.Neonates who underwent ECMO were found to have an abnormal cerebral metabolic profile, with the pattern of abnormalities suggestive of an underlying inflammatory process. Additionally, neonates who underwent venovenous ECMO had low cerebral osmolite concentrations as seen in vasogenic edema