Peripheral cord insertion is associated with adverse pregnancy outcome only when accompanied by clinically significant placental pathology.

OBJECTIVE: To examine the relationship between umbilical cord insertion site, placental pathology and adverse pregnancy outcome in a cohort of normal and complicated pregnancies. METHODS: Sonographic measurement of the cord insertion and detailed placental pathology were performed in 309 participants. Associations between cord insertion site, placental pathology and adverse pregnancy outcome (pre-eclampsia, preterm birth, small-for-gestational age) were examined. RESULTS: A total of 93 (30%) participants were identified by pathological examination to have a peripheral cord insertion site. Only 41 of the 93 (44%) peripheral cords were detected by prenatal ultrasound. Peripherally inserted cords were associated significantly (P < 0.0001) with diagnostic placental pathology (most commonly with maternal vascular malperfusion (MVM)); of which 85% had an adverse pregnancy outcome. In cases of isolated peripheral cords, without placental pathology, the incidence of adverse outcome was not statistically different when compared to those with central cord insertion and no placental pathology (31% vs 18%; P = 0.3). A peripheral cord with an abnormal umbilical artery (UA) pulsatility index (PI) corresponded to an adverse outcome in 96% of cases compared to 29% when the UA-PI was normal. CONCLUSIONS: This study demonstrates that peripheral cord insertion is often part of the spectrum of findings of MVM disease and is associated with adverse pregnancy outcome. However, adverse outcome was uncommon when there was an isolated peripheral cord insertion and no placental pathology. Therefore, additional sonographic and biochemical features of MVM should be sought when a peripheral cord is observed. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Multiple-mouse magnetic resonance imaging with cryogenic radiofrequency probes for evaluation of brain development.

Multiple-mouse magnetic resonance imaging (MRI) increases scan throughput by imaging several mice simultaneously in the same magnet bore, enabling multiple images to be obtained in the same time as a single scan. This increase in throughput enables larger studies than otherwise feasible and is particularly advantageous in longitudinal study designs where frequent imaging time points result in high demand for MRI resources. Cryogenically-cooled radiofrequency probes (CryoProbes) have been demonstrated to have significant signal-to-noise ratio benefits over comparable room temperature coils for in vivo mouse imaging. In this work, we demonstrate implementation of a multiple-mouse MRI system using CryoProbes, achieved by mounting four such coils in a 30-cm, 7-Tesla magnet bore. The approach is demonstrated for longitudinal quantification of brain structure from infancy to early adulthood in a mouse model of Sanfilippo syndrome (mucopolysaccharidosis type III), generated by knockout of the Hgsnat gene. We find that Hgsnat-/- mice have regionally increased growth rates compared to Hgsnat+/+ mice in a number of brain regions, notably including the ventricles, amygdala and superior colliculus. A strong sex dependence was also noted, with the lateral ventricle volume growing at an accelerated rate in males, but several structures in the brain parenchyma growing faster in females. This approach is broadly applicable to other mouse models of human disease and the increased throughput may be particularly beneficial in studying mouse models of neurodevelopmental disorders.

Determination of fetal heart rate short-term variation from umbilical artery Doppler waveforms.

OBJECTIVE: To evaluate the feasibility of using umbilical artery (UA) Doppler waveforms to measure fetal heart rate (FHR) short-term variation (STV) across gestation. METHODS: This was a prospective longitudinal study, conducted at two study sites, of 195 pregnancies considered low risk. Pulsed-wave Doppler of the UAs was performed at 4-weekly intervals, between 14 and 40 weeks of gestation, using a standardized imaging protocol. Up to 12 consecutive UA Doppler waveforms were analyzed using offline processing software. FHR STV was calculated using average R-R intervals extracted from the waveforms and baseline corrected for FHR. RESULTS: Baseline-corrected FHR STV increased significantly with gestational age (conditional R2 = 0.37; P < 0.0001) and was correlated inversely with FHR (conditional R2 = 0.54; P < 0.0001). The STV ranged (median (interquartile range)) from 3.5 (2.9-4.1) ms at 14-20 weeks' gestation to 6.3 (4.8-7.7) ms at 34-40 weeks' gestation. The change in heart rate STV did not differ between study sites or individual sonographers. CONCLUSIONS: UA Doppler waveforms offer a robust and feasible method to derive STV of the FHR. It should be emphasized that the UA Doppler-derived STV is not interchangeable with measurements derived with computerized cardiotocography. Accordingly, further investigations are needed to validate associations with outcome, in order to determine the value of concurrent fetal cardiovascular and heart rate evaluations that are possible with the technique described here. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Magnetic resonance spectroscopy in very preterm-born children at 4 years of age: developmental course from birth and outcomes.

PURPOSE: Brain metabolites show very rapid maturation over infancy, particularly following very preterm (VPT) birth, and can provide an index of brain injury. The utility of magnetic resonance imaging (MRS, magnetic resonance spectroscopy) in predicting outcome in VPT-born infants is largely limited to 2-year outcomes. We examined the value of MRS in VPT followed longitudinally to 4 years. METHODS: MRS datasets were acquired in 45 VPT infants (< 32 weeks gestational age) longitudinally: at birth, at term-equivalent and at 4 years of age. Using LCModel analyses in a basal ganglia voxel, we investigated metabolite ratios as a function of age, brain injury and outcome. We also studied a full-term (FT) cohort at 4 years and compared group differences with outcome. RESULTS: We found significant age-related changes in many brain metabolites in infancy, including phosphocreatine (CR)/phosphocholine (CHO), N-acetylaspartylglutamate (NAA)/CHO, myoinositol (INS)/CHO and INS/CR; there were no significant MRS differences between VPT and FT groups at 4 years of age, or differences at 4 years as a function of early brain injury or outcome. The rate of change in metabolite ratios from VPT birth to term-equivalent age did not predict outcome in the VPT children at 4 years. CONCLUSION: Brain metabolite ratios measured in VPT-born infants have shown associations with short-term outcomes, but these correlations did not extend to early childhood nor predict cognitive sequelae. The most frequently reported poor outcome in VPT-born children is cognitive difficulties starting at early school age. MRS metrics early in the infant's life do not appear to predict these longer-term outcomes.

Diffusion tensor magnetic resonance imaging in very early onset pediatric multiple sclerosis.

OBJECTIVES: Active myelination during childhood may influence the impact of multiple sclerosis (MS) on brain structural integrity. We studied normal-appearing white matter (NAWM) in children with MS onset before age 12 years using diffusion tensor (DT) magnetic resonance imaging (MRI). METHODS: DT MRI scans were obtained from 22 MS children with their first attack before age 12 years, and 31 healthy controls from two referral centers. Using probabilistic tractography, brain tissue integrity within interhemispheric, intrahemispheric, and projection tracts was compared between patients and site-matched controls. The impact of disease and age at MRI on tract NAWM fractional anisotropy (FA) and mean diffusivity (MD) values was evaluated using linear models. RESULTS: Compared to controls, pediatric MS patients had reduced FA and increased MD of the bilateral superior longitudinal fasciculus and corpus callosum (CC), without center-by-group interaction. CC NAWM average FA was correlated with brain T2 lesion volume. In controls, the majority of the tracts analyzed showed a significant increase of FA and decrease of MD with age. Such a linear correlation was lost in patients. CONCLUSIONS: In very young pediatric MS patients, DT MRI abnormalities affect brain WM tracts differentially, and are only partially correlated with focal WM lesions. Impaired maturation of WM tracts with age may be an additional factor contributing to these findings.

Regional brain atrophy in children with multiple sclerosis.

We used cross-sectional tensor-based morphometry to visualize reduced volume in the whole brains of pediatric patients with multiple sclerosis, relative to healthy controls. As a marker of local volume difference, we used the Jacobian determinant of the deformation field that maps each subject to a standard space. To properly assess abnormal differences in volume in this age group, it is necessary to account for the normal, age-related differences in brain volume. This was accomplished by computing normalized z-score Jacobian determinant values at each voxel to represent the local volume difference (in standard deviations) between an individual subject and an age- and sex-matched healthy normal population. Compared with healthy controls, pediatric patients with multiple sclerosis exhibited significantly reduced volumes within the thalamus and the splenium of the corpus callosum and significant expansions in the ventricles. While T2-weighted lesion volume was correlated with reduced splenium volume, no correlation was found between T2-weighted lesion volume and reduced thalamic volume. Reduced volumes of the optic pathways, including that of the optic tracts and optic radiations, correlated with disease duration. Our results suggest that focal inflammatory lesions may play an important role in tract degeneration, including transsynaptic degeneration.

Mouse embryonic phenotyping by morphometric analysis of MR images.

A new method is described for automatic detection of subtle morphological phenotypes in mouse embryos. Based on high-resolution magnetic resonance imaging scanning and nonlinear image alignment, this method is demonstrated by comparing the morphology of two inbred strains, C57BL/6J and 129Sv/S1ImJ, at 15.5 days postconception. Mouse embryo morphology was found to be highly amenable to this kind of analysis with very low levels (on average 110 µm) of residual anatomical variation within strains after linear differences in pose and scale are removed. Mapping of local size differences showed that C57BL/6J embryos were larger than 129Sv/S1ImJ embryos, although these differences were not uniformly distributed across the anatomy. Expressed in terms of organ volumes, heart and lung were larger in C57BL/6J embryos, while brain and liver were comparable in volume between strains. The positive relationship between organ size and embryo size was consistent for the two strains but differed by organ, with the brain and liver being the least variable. Together these findings suggest the power of this technique for detecting subtle phenotypic differences arising from mutated genes.

Comparative structural and hemodynamic analysis of vascular trees.

The availability of detailed three-dimensional images of vascular trees from mammalian organs provides a wealth of essential data for understanding the processes and mechanisms of vascular patterning. Using this detailed geometric data requires the ability to compare individual representations of vascular trees in statistically meaningful ways. This article provides some comparisons of geometry and also of simulated hemodynamics, enabling the identification of similarities and differences among 10 individual specimens (5 placenta specimens and 5 lung specimens). Similar comparisons made with a series of models (starting with the simplest and increasing in complexity) enable the identification of essential features that are needed to account for the patterns and function of vascular arborization.

Forward genetic screen of mouse reveals dominant missense mutation in the P/Q-type voltage-dependent calcium channel, CACNA1A.

Dominant mutations of the P/Q-type Ca(2+) channel (CACNA1A) underlie several human neurological disorders, including episodic ataxia type 2, familial hemiplegic migraine 1 (FHM1) and spinocerebellar ataxia 6, but have not been found previously in the mouse. Here we report the first dominant ataxic mouse model of Cacna1a mutation. This Wobbly mutant allele of Cacna1a was identified in an ethylnitrosourea (ENU) mutagenesis dominant behavioral screen. Heterozygotes exhibit ataxia from 3 weeks of age and have a normal life span. Homozygotes have a righting reflex defect from postnatal day 8 and later develop severe ataxia and die prematurely. Both heterozygotes and homozygotes exhibit cerebellar atrophy with focal reduction of the molecular layer. No obvious loss of Purkinje cells or decrease in size of the granule cell layer was observed. Real-time polymerase chain reaction revealed altered expression levels of Cacna1g, Calb2 and Th in Wobbly cerebella, but Cacna1a messenger RNA and protein levels were unchanged. Positional cloning revealed that Wobbly mice have a missense mutation leading to an arginine to leucine (R1255L) substitution, resulting in neutralization of a positively charged amino acid in repeat III of voltage sensor segment S4. The dominance of the Wobbly mutation more closely resembles patterns of CACNA1A mutation in humans than previously described mouse recessive mutants (tottering, leaner, rolling Nagoya and rocker). Positive-charge neutralization in S4 has also been shown to underlie several cases of human dominant FHM1 with ataxia. The Wobbly mutant thus highlights the importance of the voltage sensor and provides a starting point to unravel the neuropathological mechanisms of this disease.

3D visualisation and quantification by microcomputed tomography of late gestational changes in the arterial and venous feto-placental vasculature of the mouse.

This study evaluates microcomputed tomography (micro-CT) as a method to obtain quantitative three-dimensional (3D) information on the arterial and venous vasculature of the mouse placenta. Surface renderings at embryonic days (E) 13.5, 15.5, and 18.5 (full term) revealed that the arterial and venous vasculature branched within the chorionic plate whereas only the arterial vasculature deeply penetrated the placenta. Umbilical vessel diameters measured by micro-CT did not significantly differ from those measured non-invasively in vivo by ultrasound biomicroscopy. Variability in umbilical diameters, and surface area and volume measurements of arterial and venous vascular trees due to experimental error was low relative to biological variability, and significant inter-litter differences within gestational ages were detected. Furthermore, umbilical vessel diameter increased significantly and incrementally to an arterial diameter of 0.631+/-0.009 mm and a venous diameter of 0.690+/-0.018 mm at E18.5. Umbilical vein diameter was 3-9% greater than the artery, and both were significantly correlated with embryonic body weight (R> or =0.96). Surface area and volume were determined for vessels greater than the minimum resolvable diameter of 0.03 mm which therefore excluded capillaries. Arterial surface area and volume were unchanged from E13.5-15.5 but then more than doubled at E18.5 (to 170+/-13 mm(2) and 7.2+/-0.8mm(3), respectively). Venous surface areas and volumes changed similarly with development although surface areas were lower than their arterial counterparts. We conclude that micro-CT has sufficient accuracy and precision to quantify late gestational changes in the 3D structure of the arterial and venous vasculature of the mouse placenta.

Altered brain development in an early-onset murine model of Alzheimer's disease.

Murine models of Alzheimer's disease (AD) have been used to draw associations between atrophy of neural tissue and underlying pathology. In this study, the early-onset TgCRND8 mouse model of AD and littermate controls were scanned longitudinally with in vivo manganese-enhanced MRI (MEMRI) before and after the onset of amyloid plaque deposition at 12 weeks of age. Separate cohorts of mice were scanned at 1 week (ex vivo imaging) and 4 weeks (MEMRI) of age to investigate early life alterations in the brain. Contrary to our expectations, differences in neuroanatomy were found in early post-natal life, preceding plaque deposition by as much as 11 weeks. Many of these differences remained at all imaging time points, suggesting that they were programmed early in life and were unaffected by the onset of pathology. Furthermore, rather than showing atrophy, many regions of the TgCRND8 brain grew at a faster rate compared to controls. These regions contained the greatest density of amyloid plaques and reactive astrocytes. Our findings suggest that pathological processes as well as an alteration in brain development influence the TgCRND8 neuroanatomy throughout the lifespan.

Quantitative interpretation of magnetization transfer in spoiled gradient echo MRI sequences.

A method for analyzing general pulsed magnetization transfer (MT) experiments in which off-resonance saturation pulses are interleaved with on-resonance excitation pulses is presented. We apply this method to develop a steady-state signal equation for MT-weighted spoiled gradient echo sequences and consider approximations that facilitate its rapid computation. Using this equation, we assess various experimental designs for quantitatively imaging the fractional size of the restricted pool, cross-relaxation rate, and T(1) and T(2) relaxation times of the two pools in a binary spin bath system. From experiments on agar gel, this method is shown to reliably and accurately estimate the exchange and relaxation properties of a material in an imaging context, suggesting the feasibility of using this technique in vivo.

Standing-wave and RF penetration artifacts caused by elliptic geometry: an electrodynamic analysis of MRI.

Motivated by the observation that the diagonal pattern of intensity nonuniformity usually associated with linearly polarized radio-frequency (RF) coils is often present in neurological scans using circularly polarized coils, a theoretical analysis has been conducted of the intensity nonuniformity inherent in imaging an elliptically shaped object using 1.5-T magnets and circularly polarized RF coils. This first principle analysis clarifies, for the general case of conducting objects, the relationship between the excitation field and the reception sensitivity of circularly and linearly polarized coils. The results, validated experimentally using a standard spin-echo imaging sequence and an in vivo B1 field mapping technique, are shown to be accurate to within 1%-2% root mean square, suggesting that these electromagnetic interactions with the object account for most of the intensity nonuniformity observed.

A nonparametric method for automatic correction of intensity nonuniformity in MRI data.

A novel approach to correcting for intensity nonuniformity in magnetic resonance (MR) data is described that achieves high performance without requiring a model of the tissue classes present. The method has the advantage that it can be applied at an early stage in an automated data analysis, before a tissue model is available. Described as nonparametric nonuniform intensity normalization (N3), the method is independent of pulse sequence and insensitive to pathological data that might otherwise violate model assumptions. To eliminate the dependence of the field estimate on anatomy, an iterative approach is employed to estimate both the multiplicative bias field and the distribution of the true tissue intensities. The performance of this method is evaluated using both real and simulated MR data.

Design and construction of a realistic digital brain phantom.

After conception and implementation of any new medical image processing algorithm, validation is an important step to ensure that the procedure fulfills all requirements set forth at the initial design stage. Although the algorithm must be evaluated on real data, a comprehensive validation requires the additional use of simulated data since it is impossible to establish ground truth with in vivo data. Experiments with simulated data permit controlled evaluation over a wide range of conditions (e.g., different levels of noise, contrast, intensity artefacts, or geometric distortion). Such considerations have become increasingly important with the rapid growth of neuroimaging, i.e., computational analysis of brain structure and function using brain scanning methods such as positron emission tomography and magnetic resonance imaging. Since simple objects such as ellipsoids or parallelepipedes do not reflect the complexity of natural brain anatomy, we present the design and creation of a realistic, high-resolution, digital, volumetric phantom of the human brain. This three-dimensional digital brain phantom is made up of ten volumetric data sets that define the spatial distribution for different tissues (e.g., grey matter, white matter, muscle, skin, etc.), where voxel intensity is proportional to the fraction of tissue within the voxel. The digital brain phantom can be used to simulate tomographic images of the head. Since the contribution of each tissue type to each voxel in the brain phantom is known, it can be used as the gold standard to test analysis algorithms such as classification procedures which seek to identify the tissue "type" of each image voxel. Furthermore, since the same anatomical phantom may be used to drive simulators for different modalities, it is the ideal tool to test intermodality registration algorithms. The brain phantom and simulated MR images have been made publicly available on the Internet (http://www.bic.mni.mcgill.ca/brainweb).

IFPA Meeting 2013 Workshop Report II: use of 'omics' in understanding placental development, bioinformatics tools for gene expression analysis, planning and coordination of a placenta research network, placental imaging, evolutionary approaches to understanding pre-eclampsia.

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At the IFPA meeting 2013 twelve themed workshops were presented, five of which are summarized in this report. These workshops related to various aspects of placental biology but collectively covered areas of new technologies for placenta research: 1) use of 'omics' in understanding placental development and pathologies; 2) bioinformatics and use of omics technologies; 3) planning and coordination of a placenta research network; 4) clinical imaging and pathological outcomes; 5) placental evolution.

Development of a standardized MRI scoring tool for CNS demyelination in children.

BACKGROUND AND PURPOSE: The degree to which MR imaging is useful in the diagnosis of MS is predicated on standardized and reliable evaluation of MR imaging parameters. We aimed to devise items for an MR imaging scoring tool that would have high inter-rater agreement and would be straightforward to apply. MATERIALS AND METHODS: On the basis of a literature search and consensus of an expert panel, we identified 48 parameters that describe acute CNS demyelination, predict MS diagnosis, or characterize demyelinating disorder mimics. MR images of children with clinically confirmed MS, monophasic ADEM, and angiography-negative biopsy-positive small-vessel primary angiitis of the CNS were scored by 2 neuroradiologists independently, using the preliminary 48-parameter tool. Parameters with Cohen κ ≥ 0.6 and deemed important in predicting diagnosis were retained. Parameters not visualized on routine clinical imaging or not important in differentiating MS, ADEM, and SV-cPACNS were discarded. RESULTS: Of 65 eligible patients, 55 children were enrolled (16 with monophasic ADEM, 27 with MS, 12 with SV-cPACNS); 10 were excluded (6 had hard-copy films, 4 did not meet MR imaging quality requirements). Of the 48 parameters, 16 were retained in the final scoring tool. The remaining 28 parameters were discarded: 4 had κ < 0.6 and were not deemed useful in predicting diagnosis; 9 were not visible on routinely acquired clinical images; and 15 had inter-rater agreement ≥0.6 but were not useful in differentiating monophasic ADEM, MS, and SV-cPACNS. CONCLUSIONS: We propose a 16-parameter MR imaging scoring tool that is straightforward to apply in the clinical setting and demonstrates high inter-rater agreement.

Validation of MRI predictors of multiple sclerosis diagnosis in children with acute CNS demyelination.

BACKGROUND: In a recent Canadian prospective study of children with acute demyelinating syndromes (ADS), we demonstrated that the presence of T2 periventricular and T1-hypointense lesions predicted MS diagnosis. We aimed to validate these predictors in a Dutch cohort of children with ADS. METHODS: Participants with ADS were identified from a prospective cohort or archived dataset. MS was diagnosed based on clinical or MRI evidence of relapsing disease. Baseline MRI scans were evaluated for the presence of the two predictive parameters. Sensitivity, specificity, positive (LR+) and negative likelihood ratios (LR-), and positive (PPV) and negative predictive value (NPV) were calculated to evaluate the performance of the MRI parameters at classifying children as having MS or monophasic demyelination. FINDINGS: Of 115 children identified with ADS between December 1993 and December 2009, MRI scans from 87 children (45 prospective; 47 archived) were evaluated; scans of 28 children were excluded due to incomplete or poor quality imaging. Mean duration of observation was longer in the archived group (7.1 years, SD 3.5) than the prospective cohort (3.3 years, SD 1.4). 30 children were diagnosed with MS. Performance of the parameters was not statistically different between the prospective cohort (sensitivity 93.3% [68.1-99.8]; specificity 86.7% [69.3-96.2]; LR+ 7.0 [2.8-17.6]; LR- 0.08 [0.01-0.5]; PPV 77.8% [52.4-93.6]; NPV 96.3% [81.0-99.9]) and archived group (sensitivity 66.7% [38.4-88.2]; specificity 85.2% [66.3-95.8]; LR+ 4.5 [1.7-11.9]; LR- 0.4 [0.2-0.8]; PPV 71.4% [41.9-91.6]; NPV 82.1% [63.1-93.9]). INTERPRETATION: In an independent Dutch cohort, we confirm that the presence of ≥1 T2 periventricular and ≥1 T1-hypointense lesions reliably identifies children with MS. FUNDING: Dutch MS Research Foundation.

Reduced head and brain size for age and disproportionately smaller thalami in child-onset MS.

OBJECTIVE: Whole brain and regional volume measurement methods were used to quantify white matter, gray matter, and deep gray matter structure volumes in a population of patients with pediatric-onset multiple sclerosis (MS). METHODS: Subjects included 38 patients (mean age 15.2 ± 2.4 years) and 33 age- and sex-matched healthy control (HC) participants. MRI measures included intracranial volume, normalized brain volume, normalized white and gray matter volume, and volumes of the thalamus, globus pallidus, putamen, and caudate. Because these volumes vary across age and sex in children, we normalized the volume measurements for MS and control groups by computing z scores using normative values obtained from healthy children enrolled in the MRI Study of Normal Brain Development. RESULTS: The intracranial volume z score was significantly lower in the patients with MS (-0.45 ± 1.16; mean ± SD) compared with the HC participants (+0.25 ± 0.98; p = 0.01). Patients with MS also demonstrated significant decreases in normalized brain volume z scores (-1.09 ± 1.49 vs -0.05 ± 1.22; p = 0.002). After correction for global brain volume, thalamic volumes in the MS population remained lower than those of HCs (-0.68 ± 1.72 vs 0.15 ± 1.35; p = 0.02), indicating an even greater loss of thalamic tissue relative to more global brain measures. Moderate correlations were found between T2-weighted lesion load and normalized thalamic volumes (r = -0.44, p < 0.01) and normalized brain volume (r = -0.47, p < 0.01) and between disease duration and normalized thalamic volume (r = -0.58, p < 0.001) and normalized brain volume (r = -0.46, p < 0.01). CONCLUSIONS: When compared with age- and sex-matched control subjects, the onset of MS during childhood is associated with a smaller overall head size, brain volume, and an even smaller thalamic volume.