A systematic review of immune-based interventions for perinatal neuroprotection: closing the gap between animal studies and human trials.

BACKGROUND: Perinatal infection/inflammation is associated with a high risk for neurological injury and neurodevelopmental impairment after birth. Despite a growing preclinical evidence base, anti-inflammatory interventions have not been established in clinical practice, partly because of the range of potential targets. We therefore systematically reviewed preclinical studies of immunomodulation to improve neurological outcomes in the perinatal brain and assessed their therapeutic potential. METHODS: We reviewed relevant studies published from January 2012 to July 2023 using PubMed, Medline (OvidSP) and EMBASE databases. Studies were assessed for risk of bias using the SYRCLE risk of bias assessment tool (PROSPERO; registration number CRD42023395690). RESULTS: Forty preclinical publications using 12 models of perinatal neuroinflammation were identified and divided into 59 individual studies. Twenty-seven anti-inflammatory agents in 19 categories were investigated. Forty-five (76%) of 59 studies reported neuroprotection, from all 19 categories of therapeutics. Notably, 10/10 (100%) studies investigating anti-interleukin (IL)-1 therapies reported improved outcome, whereas half of the studies using corticosteroids (5/10; 50%) reported no improvement or worse outcomes with treatment. Most studies (49/59, 83%) did not control core body temperature (a known potential confounder), and 25 of 59 studies (42%) did not report the sex of subjects. Many studies did not clearly state whether they controlled for potential study bias. CONCLUSION: Anti-inflammatory therapies are promising candidates for treatment or even prevention of perinatal brain injury. Our analysis highlights key knowledge gaps and opportunities to improve preclinical study design that must be addressed to support clinical translation.

Long-Term Mechanical Ventilation in Neonates: A 10-Year Overview and Predictive Model.

Objectives: Significant resources are devoted to neonatal prolonged mechanical ventilation (NPMV), but little is known about the outcomes in those children. Our primary objective was to describe the NPMV respiratory, digestive, and neurological outcomes at 18 months corrected age. Our second objective was on the early identification of which patients, among the NPMV cohort, will need to be ventilated for ≥125 days, which corresponded to the 75th percentile in the preliminary data, and to describe that subgroup. Methods: In this retrospective cohort study, we included all children born between 2004 and 2013 who had a NPMV (≥21 days of invasive or noninvasive respiratory support reached between 40 and 44 weeks of postconceptional age). We used random forests, logistic regression with penalization, naive Bayes, and XGBoost to predict which patients will need ≥125 days of ventilation. We used a Monte Carlo cross validation. Results: We included 164 patients. Of which, 40% (n = 66) were female, and the median gestational age was 29 weeks [interquartile range (IQR): 26-36 weeks] with a bimodal distribution. Median ventilation days were 104 (IQR: 66-139 days). The most frequently associated diagnoses were pulmonary hypertension (43%), early pulmonary dysplasia (41%), and lobar emphysema (37%). At 18 months corrected age, 29% (n = 47) had died, 59% (n = 97) were free of any respiratory support, and 45% (n = 74) were exclusively orally fed. A moderate area under the ROC curve of 0.65 (95% CI: 0.54-0.72) for identifying patients in need of ≥125 days of ventilation at inclusion was achieved by random forests classifiers. Among the 26 measured at inclusion, the most contributive ones were PCO2, inspired O2 concentration, and gestational age. At 18 months corrected age, patients ventilated for ≥125 days had a lower respiratory weaning success (76 vs. 87%, P = 0.05), lower exclusive oral feeding proportion (51 vs. 84%, P < 0.001), and a higher neurological impairment (median Pediatric Cerebral Performance Category score 3 vs. 2, P = 0.008) than patients ventilated for < 125 days. Conclusion: NPMV is a severe condition with a high risk of mortality, neurological impairment, and oral feed delay at 18 months. Most survivors are weaned of any respiratory support. We identified the risk factors that allow for the early identification of the most at-risk children of long-term ventilation with a moderate discrimination.

User-independent diffusion tensor imaging analysis pipelines in a rat model presenting ventriculomegalia: A comparison study.

Automated analysis of diffusion tensor imaging (DTI) data is an appealing way to process large datasets in an unbiased manner. However, automation can sometimes be linked to a lack of interpretability. Two whole-brain, automated and voxelwise methods exist: voxel-based analysis (VBA) and tract-based spatial statistics (TBSS). In VBA, the amount of smoothing has been shown to influence the results. TBSS is free of this step, but a projection procedure is introduced to correct for residual misalignments. This projection assigns the local highest fractional anisotropy (FA) value to the mean FA skeleton, which represents white matter tract centers. For both methods, the normalization procedure has a major impact. These issues are well documented in humans but, to our knowledge, not in rodents. In this study, we assessed the quality of three different registration algorithms (ANTs SyN, DTI-TK and FNIRT) using study-specific templates and their impact on automated analysis methods (VBA and TBSS) in a rat pup model of diffuse white matter injury presenting large unilateral deformations. VBA and TBSS results were stable and anatomically coherent across the three pipelines. For VBA, in regions around the large deformations, interpretability was limited because of the increased partial volume effect. With TBSS, two of the three pipelines found a significant decrease in axial diffusivity (AD) at the known injury site. These results demonstrate that automated voxelwise analyses can be used in an animal model with large deformations.

Definition and quantification of acute inflammatory white matter injury in the immature brain by MRI/MRS at high magnetic field.

BACKGROUND: Lipopolysaccharide (LPS) injection in the corpus callosum (CC) of rat pups results in diffuse white matter injury similar to the main neuropathology of preterm infants. The aim of this study was to characterize the structural and metabolic markers of acute inflammatory injury by high-field magnetic resonance imaging (MRI) magnetic resonance spectroscopy (MRS) in vivo. METHODS: Twenty-four hours after a 1-mg/kg injection of LPS in postnatal day 3 rat pups, diffusion tensor imaging and proton nuclear magnetic spectroscopy ((1)H NMR) were analyzed in conjunction to determine markers of cell death and inflammation using immunohistochemistry and gene expression. RESULTS: MRI and MRS in the CC revealed an increase in lactate and free lipids and a decrease of the apparent diffusion coefficient. Detailed evaluation of the CC showed a marked apoptotic response assessed by fractin expression. Interestingly, the degree of reduction in the apparent diffusion coefficient correlated strongly with the natural logarithm of fractin expression, in the same region of interest. LPS injection further resulted in increased activated microglia clustered in the cingulum, widespread astrogliosis, and increased expression of genes for interleukin (IL)-1, IL-6, and tumor necrosis factor. CONCLUSION: This model was able to reproduce the typical MRI hallmarks of acute diffuse white matter injury seen in preterm infants and allowed the evaluation of in vivo biomarkers of acute neuropathology after inflammatory challenge.

High-field diffusion tensor imaging characterization of cerebral white matter injury in lipopolysaccharide-exposed fetal sheep.

BACKGROUND: In gyrencephalic species such as sheep, precise anatomical and microstructural characterization of the consequences of fetal inflammation remains scarce. The goal of this study was to characterize changes in white matter (WM) structure using advanced magnetic resonance imaging (MRI) following lipopolysaccharide (LPS) exposure in the preterm-equivalent fetal sheep. METHODS: Preterm (0.7 gestation) fetal sheep received vehicle (Sham group) or LPS (LPS group), and fetal brains were collected 10 d later for subsequent ex vivo MRI. T1-weighted (T(1)W), T2-weighted (T(2)W), and diffusion tensor imaging (DTI) data were collected. RESULTS: Fetuses exposed to LPS exhibited reductions in WM volume and corpus callosum thickness at 10 d recovery. Characteristic patterns of diffuse and focal WM lesions (necrosis or cysts) could be identified by various T1, T2, and DTI signal changes. CONCLUSION: Fetal LPS exposure induces a pattern of injury characterized by diffuse and focal WM injury that closely reproduces that observed clinically in preterm infants. This work provides anatomical and microstructural MRI assessment, as well as histopathological correlates, of the consequences of LPS exposure in an animal model with a WM structure similar to that of the human brain. This work will help to further our understanding of MRI changes in preterm infants.