Decoding 22q11.2: prenatal profiling and first-trimester risk assessment in Danish nationwide cohort.

OBJECTIVES: To examine the distribution of nuchal translucency thickness (NT), free ß-human chorionic gonadotropin (ß-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in pregnancies with a fetal 22q11.2 aberration. Furthermore, the performance of combined first-trimester screening (cFTS) and a new risk algorithm targeting 22q11.2 deletions in detecting affected pregnancies was evaluated. Finally, prenatal malformations and pregnancy outcome were assessed. METHODS: This was a nationwide registry-based cohort study of all pregnancies that underwent prenatal screening with a due date between January 2008 and December 2018 in Denmark. All cases with a fetal 22q11.2 deletion or duplication (hg19 chr22:18.9mio-25.0mio) diagnosed pre- or postnatally or following pregnancy loss or termination of pregnancy were retrieved from the Danish Cytogenetic Central Register and linked with pregnancy data from the Danish Fetal Medicine Database. Fetal and maternal characteristics, including cFTS results and pregnancy outcome, of pregnancies with any 22q11.2 deletion or duplication (LCR22-A to -H) and pregnancies with a classic deletion or duplication (LCR22-A to -D) diagnosed by chromosomal microarray were compared with those of a chromosomally normal reference group. A risk algorithm was developed for assessing patient-specific risks for classic 22q11.2 deletions based on NT, PAPP-A and ß-hCG. Detection rates and false-positive rates at different risk cut-offs were calculated. RESULTS: We included data on 143 pregnancies with a fetal 22q11.2 aberration, of which 97 were deletions (54 classic) and 46 were duplications (32 classic). NT was significantly increased in fetuses with a classic deletion (mean, 1.89 mm), those with any deletion (mean, 1.78 mm) and those with any duplication (mean, 1.86 mm) compared to the reference group (mean, 1.65 mm). ß-hCG multiples of the median (MoM) was decreased in all 22q11.2 subgroups compared with the reference group (mean, 1.02) and reached significance in pregnancies with a classic deletion and those with any deletion (mean, 0.77 and 0.71, respectively). PAPP-A MoM was significantly decreased in pregnancies with a classic duplication and those with any duplication (mean, 0.57 and 0.63, respectively), and was significantly increased in pregnancies with a classic deletion and those with any deletion (mean, 1.34 and 1.16, respectively), compared to reference pregnancies (mean, 1.01). The screen-positive rate by cFTS was significantly increased in pregnancies with a classic deletion (13.7%), any deletion (12.5%), a classic duplication (46.9%) or any duplication (37.8%) compared to the reference group (4.5%). A risk algorithm targeting classic 22q11.2 deletions more than doubled the prenatal detection rate of classic 22q11.2 deletions, but with a substantial increase in the false-positive rate. Structural malformations were detected in 41%, 35%, 17% and 25% of the pregnancies with a classic deletion, any deletion, classic duplication or any duplication, respectively. Pregnancy loss occurred in 40% of pregnancies with a classic deletion and 5% of those with a classic duplication diagnosed prenatally or following pregnancy loss. CONCLUSIONS: The distribution of cFTS markers in pregnancies with a classic 22q11.2 duplication resembles that of the common trisomies, with decreased levels of PAPP-A. However, classic 22q11.2 deletions are associated with increased levels of PAPP-A, which likely limits early prenatal detection using the current cFTS risk algorithm. The scope for improving early detection of classic 22q11.2 deletions using targeted risk algorithms based on NT, PAPP-A and ß-hCG is limited. This demonstrates the capability, but also the limitations, of cFTS markers in detecting atypical chromosomal anomalies, which is important knowledge when designing new prenatal screening programs. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Perfusion MRI (dynamic susceptibility contrast imaging) with different measurement approaches for the evaluation of blood flow and blood volume in human gliomas.

BACKGROUND: Perfusion magnetic resonance imaging (MRI) is increasingly used in the evaluation of brain tumors. Relative cerebral blood volume (rCBV) is usually obtained by dynamic susceptibility contrast (DSC) MRI using normal appearing white matter as reference region. The emerging perfusion technique arterial spin labelling (ASL) presently provides measurement only of cerebral blood flow (CBF), which has not been widely used in human brain tumor studies. PURPOSE: To assess if measurement of blood flow is comparable with measurement of blood volume in human biopsy-proven gliomas obtained by DSC-MRI using two different regions for normalization and two different measurement approaches. MATERIAL AND METHODS: Retrospective study of 61 patients with different types of gliomas examined with DSC perfusion MRI. Regions of interest (ROIs) were placed in tumor portions with maximum perfusion on rCBF and rCBV maps, with contralateral normal appearing white matter and cerebellum as reference regions. Larger ROIs were drawn for histogram analyses. The type and grade of the gliomas were obtained by histopathology. Statistical comparison was made between diffuse astrocytomas, anaplastic astrocytomas, and glioblastomas. RESULTS: rCBF and rCBV measurements obtained with the maximum perfusion method were correlated when normalized to white matter (r = 0.60) and to the cerebellum (r = 0.49). Histogram analyses of rCBF and rCBV showed that mean and median values as well as skewness and peak position were correlated (0.61 < r < 0.93), whereas for kurtosis and peak height, the correlation coefficient was about 0.3 when comparing rCBF and rCBV values for the same reference region. Neither rCBF nor rCBV quantification provided a statistically significant difference between the three types of gliomas. However, both rCBF and rCBV tended to increase with tumor grade and to be lower in patients who had undergone resection/treatment. CONCLUSION: rCBF measurements normalized to white matter or cerebellum are comparable with the established rCBV measurements used for the clinical evaluation of cerebral gliomas.

Geometric and mechanosensory properties of the sigmoid colon evaluated with magnetic resonance imaging.

The aim of this study was to use magnetic resonance imaging (MRI) to evaluate the three-dimensional geometry and mechanosensory properties of the sigmoid colon. The sigmoid colon was stepwise distended by a water-filled bag in eight subjects. Simultaneous MRI, bag pressure recording and sensory assessment were performed before and after smooth muscle relaxation with butylscopolamine. The surface distributions of principal curvature radii, wall thickness, tension, stress and circumferential strain were calculated. The geometry of the distended sigmoid colon was complex and the spatial distributions of the biomechanical parameters were non-homogeneous. The circumferential length, strain, pressure and wall stress increased as a function of bag volume (all P < 0.001). In response to butylscopolamine, the pressure and wall stress were reduced (P < 0.05) and the stress-strain curves were shifted to the right. The sensory response was a linear function of the biomechanical parameters (all P < 0.001) and decreased in response to butylscopolamine as a function of volume (P = 0.02). The stimulus-response data indicate that the mechanosensitive afferents are affected by smooth muscle tone. The present study provides a method for characterizing the complex geometry and mechanical properties of the sigmoid colon, including the role of smooth muscle tone. This may be valuable in understanding of the biomechanical and mechanosensory functions in colonic diseases.

Three-dimensional biomechanical properties of the human rectum evaluated with magnetic resonance imaging.

A method to evaluate the three-dimensional (3-D) geometry of the human gastrointestinal wall may be valuable for understanding tissue biomechanics, mechano-sensation and function. In this paper we present a magnetic resonance imaging (MRI) based method to determine rectal geometry and validation of data obtained in three volunteers. A specially designed rectal bag was filled in a stepwise manner while MRI and bag pressure were recorded. 3-D models of curvatures, radii of curvature, tension and stress were generated and the circumferential and longitudinal strains were calculated. The computed bag volumes corresponded to the infused volumes. A pronounced bag elongation and decrease in wall thickness was observed during the bag filling. The spatial distributions of the biomechanical parameters were distinctly different between individuals and non-homogeneous throughout the rectal wall due to its complex geometry. The average tension and stress increased as a function of infused volume and circumferential strain. The present study provides a method for characterizing the complex in vivo 3-D geometry of the human rectum. The non-homogenous spatial curvature distribution suggests that simple estimates of tension based on pressure and volume do not reflect the true 3-D biomechanical properties of the rectum.

Normalization of markers for dopamine innervation in striatum of MPTP-lesioned miniature pigs with intrastriatal grafts.

As part of the DaNeX study, the uptake and binding of several positron emitting tracers was recorded in brain of healthy Göttingen minipigs, in minipigs with a syndrome of parkinsonism due to MPTP intoxication, and in parkinsonian minipigs which had received intrastriatal grafts of mesencephalic neurons from fetal pigs. The specific binding of [11C]NS 2214 to catecholamine uptake sites was reduced by two thirds in striatum of the intoxicated animals, while the rate constant for the decarboxylation of [18F]fluorodopa was reduced by 50% in the intoxicated animals. Several months after grafting, both pre-synaptic markers of dopamine fibres were normal in striatum. Dopamine depletion or grafting were without effect on the cerebral perfusion rate, measured with [15O]-water, did not alter the rate of oxygen metabolism (CMRO2) in brain, and did not alter the binding potential of tracers for dopamine D1 or D2 receptors in pig striatum. However, the grafting was associated with a local increase in the binding of [11C]PK 11195, a tracer for reactive gliosis, suggesting that an immunological reaction occurs at the site of graft, which might potentially have reduced the graft patency. However, this apparent immunological response did not preclude the re-establishment of normal [18F]fluorodopa and [11C]NS 2214 uptake in the allografted striatum.