Enhanced Spatial Fuzzy C-Means Algorithm for Brain Tissue Segmentation in T1 Images.

Magnetic Resonance Imaging (MRI) plays an important role in neurology, particularly in the precise segmentation of brain tissues. Accurate segmentation is crucial for diagnosing brain injuries and neurodegenerative conditions. We introduce an Enhanced Spatial Fuzzy C-means (esFCM) algorithm for 3D T1 MRI segmentation to three tissues, i.e. White Matter (WM), Gray Matter (GM), and Cerebrospinal Fluid (CSF). The esFCM employs a weighted least square algorithm utilizing the Structural Similarity Index (SSIM) for polynomial bias field correction. It also takes advantage of the information from the membership function of the last iteration to compute neighborhood impact. This strategic refinement enhances the algorithm's adaptability to complex image structures, effectively addressing challenges such as intensity irregularities and contributing to heightened segmentation accuracy. We compare the segmentation accuracy of esFCM against four variants of FCM, Gaussian Mixture Model (GMM) and FSL and ANTs algorithms using four various dataset, employing three measurement criteria. Comparative assessments underscore esFCM's superior performance, particularly in scenarios involving added noise and bias fields.The obtained results emphasize the significant potential of the proposed method in the segmentation of MRI images.

Corpus callosum long-term biometry in very preterm children related to cognitive and motor outcomes.

BACKGROUND: The corpus callosum (CC) is suggested as an indirect biomarker of white matter volume, which is often affected in preterm birth. However, diagnosing mild white matter injury is challenging. METHODS: We studied 124 children born preterm (mean age: 8.4 ± 1.1 years), using MRI to assess CC measurements and cognitive/motor outcomes based on the Wechsler Intelligence Scale for Children-V (WPPSI-V) and Movement Assessment Battery for Children-2 (MABC-2). RESULTS: Children with normal outcomes exhibited greater height (10.2 ± 2.1 mm vs. 9.4 ± 2.3 mm; p = 0.01) and fractional anisotropy at splenium (895[680-1000] vs 860.5[342-1000]) and total CC length (69.1 ± 4.8 mm vs. 67.3 ± 5.1 mm; p = 0.02) compared to those with adverse outcomes. All measured CC areas were smaller in the adverse outcome group. Models incorporating posterior CC measurements demonstrated the highest specificity (83.3% Sp, AUC: 0.65) for predicting neurological outcomes. CC length and splenium height were the only linear measurements associated with manual dexterity and total MABC-2 score while both the latter and genu were related with Full-Scale Intelligence Quotient. CONCLUSIONS: CC biometry in children born very preterm at school-age is associated with outcomes and exhibits a specific subregion alteration pattern. The posterior CC may serve as an important neurodevelopmental biomarker in very preterm infants. IMPACT: The corpus callosum has the potential to serve as a reliable and easily measurable biomarker of white matter integrity in very preterm children. Estimating diffuse white matter injury in preterm infants using conventional MRI sequences is not always conclusive. The biometry of the posterior part of the corpus callosum is associated with cognitive and certain motor outcomes at school age in children born very preterm. Length and splenium measurements seem to serve as reliable biomarkers for assessing neurological outcomes in this population.

Glycogen Synthase Kinase-3ß Inhibitor VP3.15 Ameliorates Neurogenesis, Neuronal Loss and Cognitive Impairment in a Model of Germinal Matrix-intraventricular Hemorrhage of the Preterm Newborn.

Advances in neonatology have significantly reduced mortality rates due to prematurity. However, complications of prematurity have barely changed in recent decades. Germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most severe complications of prematurity, and these children are prone to suffer short- and long-term sequelae, including cerebral palsy, cognitive and motor impairments, or neuropsychiatric disorders. Nevertheless, GM-IVH has no successful treatment. VP3.15 is a small, heterocyclic molecule of the 5-imino-1,2,4-thiadiazole family with a dual action as a phosphodiesterase 7 and glycogen synthase kinase-3ß (GSK-3ß) inhibitor. VP3.15 reduces neuroinflammation and neuronal loss in other neurodegenerative disorders and might ameliorate complications associated with GM-IVH. We administered VP3.15 to a mouse model of GM-IVH. VP3.15 reduces the presence of hemorrhages and microglia in the short (P14) and long (P110) term. It ameliorates brain atrophy and ventricle enlargement while limiting tau hyperphosphorylation and neuronal and myelin basic protein loss. VP3.15 also improves proliferation and neurogenesis as well as cognition after the insult. Interestingly, plasma gelsolin levels, a feasible biomarker of brain damage, improved after VP3.15 treatment. Altogether, our data support the beneficial effects of VP3.15 in GM-IVH by ameliorating brain neuroinflammatory, vascular and white matter damage, ultimately improving cognitive impairment associated with GM-IVH.

NeoCam: An Edge-Cloud Platform for Non-Invasive Real-Time Monitoring in Neonatal Intensive Care Units.

In this work we introduce NeoCam, an open source hardware-software platform for video-based monitoring of preterms infants in Neonatal Intensive Care Units (NICUs). NeoCam includes an edge computing device that performs video acquisition and processing in real-time. Compared to other proposed solutions, it has the advantage of handling data more efficiently by performing most of the processing on the device, including proper anonymisation for better compliance with privacy regulations. In addition, it allows to perform various video analysis tasks of clinical interest in parallel at speeds of between 20 and 30 frames-per-second. We introduce algorithms to measure without contact the breathing rate, motor activity, body pose and emotional status of the infants. For breathing rate, our system shows good agreement with existing methods provided there is sufficient light and proper imaging conditions. Models for motor activity and stress detection are new to the best of our knowledge. NeoCam has been tested on preterms in the NICU of the University Hospital Puerta del Mar (Cádiz, Spain), and we report the lessons learned from this trial.

Relationship of early brain growth pattern measured by ultrasound with neurological outcome at two years of age in very low birth weight infants.

The purpose of this study is to define the impact of early brain growth trajectory in very low birth weight infants (VLBWI) on neurological prognosis at 2 years, assessed using sequential ultrasound (US) scans. This is a prospective cohort study with consecutive inclusion of VLBWI ≤ 32 weeks gestational age and ≤ 1500 g at birth. Total brain volume (TBV) was assessed using sequential 3D-US from birth to discharge. Prognosis at 2 years (corrected age) was assessed using the Bayley Scales of Infant and Toddler Development Third Edition. TBV showed slower growth with postmenstrual age (PMA) in those VLBWI who had an adverse cognitive prognosis compared to those with good cognitive prognosis (mean difference in TBV between prognostic groups from 4.56 cm3 at 28 weeks to 42.58 cm3 at 43 weeks) as well as in those with adverse language prognosis (mean difference in TBV from 2.21 cm3 at 28 weeks to 26.98 cm3 at 43 weeks) although other variables showed more impact than TBV on language prognosis (gestational age at birth, brain injury at term, and socioeconomic status). No association was found between TBV and motor prognosis. Brain growth rate was also significantly higher in those VLBWI who presented good cognitive scores (18.78 + (0.33 × (PMA-33)) cm3/week) compared to those with adverse cognitive outcome (13.73 + (0.64 × (PMA-33)) cm3/week).  Conclusion: Early altered brain growth is associated with poor cognitive prognosis at 2 years of age. Using sequential US monitoring, we can detect early brain growth deviation in patients who will have adverse cognitive outcomes. What is known: • The prediction of neurodevelopmental outcome of VLBWI is mostly based on the presence of brain injury in US and structural magnetic resonance imaging (MRI) at term. • Some studies have related brain volume measured on MRI at term with neurodevelopment outcome. What is new: • VLBWI with adverse cognitive prognosis at two years of age present smaller brain volumes detectable by sequential US during NICU admission. • Brain volume can be estimated from 2D and 3D US and has prognostic value in VLBWI.

A deep sift convolutional neural networks for total brain volume estimation from 3D ultrasound images.

Preterm infants are a highly vulnerable population. The total brain volume (TBV) of these infants can be accurately estimated by brain ultrasound (US) imaging which enables a longitudinal study of early brain growth during Neonatal Intensive Care (NICU) admission. Automatic estimation of TBV from 3D images increases the diagnosis speed and evades the necessity for an expert to manually segment 3D images, which is a sophisticated and time consuming task. We develop a deep-learning approach to estimate TBV from 3D ultrasound images. It benefits from deep convolutional neural networks (CNN) with dilated residual connections and an additional layer, inspired by the fuzzy c-Means (FCM), to further separate the features into different regions, i.e. sift layer. Therefore, we call this method deep-sift convolutional neural networks (DSCNN). The proposed method is validated against three state-of-the-art methods including AlexNet-3D, ResNet-3D, and VGG-3D, for TBV estimation using two datasets acquired from two different ultrasound devices. The results highlight a strong correlation between the predictions and the observed TBV values. The regression activation maps are used to interpret DSCNN, allowing TBV estimation by exploring those pixels that are more consistent and plausible from an anatomical standpoint. Therefore, it can be used for direct estimation of TBV from 3D images without needing further image segmentation.

Ultrasonographic Estimation of Ventricular Volume in Infants Born Preterm with Posthemorrhagic Ventricular Dilatation: A Nested Substudy of the Randomized Controlled Early Versus Late Ventricular Intervention Study (ELVIS) Trial.

OBJECTIVE: To study the potential role of ventricular volume (VV) estimation in the management of posthemorrhagic ventricular dilatation related to the need for ventriculoperitoneal (VP)-shunt insertion and 2-year neurodevelopmental outcome in infants born preterm. STUDY DESIGN: We included 59 patients from the Early vs Late Ventricular Intervention Study from 4 participating centers. VV was manually segmented in 209 3-dimensional ultrasound scans and estimated from 2-dimensional ultrasound linear measurements in a total of 1226 ultrasounds. We studied the association of both linear measurements and VV to the need for VP shunt and 2-year neurodevelopmental outcome in the overall cohort and in the 29 infants who needed insertion of a reservoir. We used general estimating equations to account for repeated measures per individual. RESULTS: Maximum pre-reservoir VV (ß coefficient = 0.185, P = .0001) and gestational age at birth (ß = -0.338; P = .0001) were related to the need for VP shunt. The estimated optimal single VV measurement cut point of 17 cm3 correctly classified 79.31% with an area under the curve of 0.76 (CI 95% 0.74-0.79). Maximum VV (ß = 0.027; P = .012) together with VP shunt insertion (ß = 3.773; P = .007) and gestational age (ß = -0.273; P = .0001) were related to cognitive outcome at 2 years. Maximum ventricular index and anterior horn width before reservoir insertion were independently associated with the need of VP shunt and the proposed threshold groups in the Early vs Late Ventricular Intervention Study trial were associated with long-term outcome. CONCLUSIONS: Pre-reservoir VV measurements were associated with the need for VP-shunt insertion and 2-year cognitive outcome among infants born preterm with posthemorrhagic ventricular dilatation. TRIAL REGISTRATION: ISRCTN43171322.

Massive Neonatal Arterial Ischemic Stroke.

BACKGROUND: Massive infarction in adults is a devastating entity characterized by signs of extreme swelling of the brain's parenchyma. We explored whether a similar entity exists in neonates, which we call massive neonatal arterial ischemic stroke (M-NAIS), and assess its potential clinical implications. METHODS: Prospective multicenter cohort study comprising 48 neonates with gestational age ≥35 weeks with middle cerebral artery (MCA) NAIS was performed. Diagnosis with magnetic resonance imaging (MRI) was performed within the first three days after symptom onset. The presence of signs of a space-occupying mass, such as brain midline shift and/or ventricular and/or extra-axial space collapse, was recorded. The volume of the infarct and brain midline shift were determined with semiautomatic procedures. Neurodevelopment was assessed at age 24 months. RESULTS: Fifteen (31%) neonates presented MRI signs of a space-occupying mass effect and were considered to have an M-NAIS. The relative volume (infarct volume/total brain volume) of the infarct was on average significantly greater in the M-NAIS subgroup (29% vs 4.9%, P < 0.001). Patients with M-NAIS consistently presented lesions involving the M1 arterial territory of the MCA and showed more apneic and tonic seizures, which had an earlier onset and lasted longer. Moderate to severe adverse neurodevelopmental outcomes were present in most M-NAIS cases (79% vs 6%, P < 0.001). CONCLUSIONS: M-NAIS appears to be a distinctive subtype of neonatal infarction, defined by characteristic neuroimaging signs. Neonates with M-NAIS frequently present a moderate to severe adverse outcome. Early M-NAIS identification would allow for prompt, specific rehabilitation interventions and would provide more accurate prognostic information to families.

Assessment of the perception of vertical subjectivity in children born preterm.

Children born preterm have increased rates of paediatric mortality and morbidity. Prematurity has been associated with impaired visual perception and visuo-motor integration. The alteration of the perception of verticality translates into alterations of the vestibular system at central and/or peripheral level, which may manifest itself in symptoms such as imbalance, dizziness or even vertigo. The aim of this study was to compare subjective visual vertical (SVV) test scores in children born preterm with those of children born at term at ages between 7 and 10. One hundred ten children with no neurodevelopmental disorder of 7 to 10 years of age were studied using a mobile application on a smartphone attached to a wall by means of a rotating plate. The SVV test was compared between two groups: a group of 55 preterm children (53 very preterm children born under 32 weeks of gestational age and 2 preterm with very low birth weight) and another group of 55 children born at term (after 37 weeks of gestational age). The SVV results were analysed for comparison with respect to prematurity, sex and age. We found no significant differences in the SVV study in the comparison between preterm and term children. In addition, no significant differences were observed regarding sex or age between 7 and 10 years.  Conclusion: We found no alterations in the perception of vertical subjectivity in children between 7 and 10 years of age, with antecedents of very preterm birth and/or very low birth weight. What is Known: • The different studies published so far suggest the existence of balance disorders in premature children, although in most of these studies the children are examined at an age when the vestibular system is not mature and with non-specific tests for the study of the vestibular system. What is New: • We compared the results of the subjective visual vertical (SVV) test in a group of 55 preterm children (53 very preterm children born under 32 weeks of gestational age and 2 preterm with very low weight at birth) and in a group of 55 children born at term (after 37 weeks of gestational age), at the ages of 7 to 10 years and observed no differences. • We conclude that, if there had been any vestibular alterations due to very premature birth, these must have been compensated by the age of 7.

Ultrasonographic evaluation of the early brain growth pattern in very low birth weight infants.

BACKGROUND: Preterm infants develop smaller brain volumes compared to term newborns. Our aim is to study early brain growth related to perinatal factors in very low birth weight infants (VLBWI). METHODS: Manual segmentation of total brain volume (TBV) was performed in weekly 3D-ultrasonographies in our cohort of VLBWI. We studied the brain growth pattern related to term magnetic resonance image (term-MRI). RESULTS: We found different brain growth trajectories, with smaller brain volumes and a decrease in brain growth rate in those VLBWI who would later have an abnormal term-MRI (mean TBV 190.68 vs. 213.9 cm3; P = 0.0001 and mean TBV growth rate 14.35 (±1.27) vs. 16.94 (±2.29) cm3/week; P = 0.0001). TBV in those with normal term-MRI was related to gestational age (GA), being small for gestational age (SGA), sex, and duration of parenteral nutrition (TPN) while in those with abnormal term-MRI findings it was related to GA, SGA, TPN, and comorbidities. We found a deceleration in brain growth rate in those with ≥3 comorbidities. CONCLUSIONS: An altered brain growth pattern in VLBWI who subsequently present worst scores on term-MRI is related to GA, being SGA and comorbidities. Early ultrasonographic monitoring of TBV could be useful to detect deviated patterns of brain growth. IMPACT STATEMENT: We describe the brain growth pattern in very low birth weight infants during their first postnatal weeks. Brain growth may be affected in the presence of certain perinatal factors and comorbidities, conditioning a deviation of the normal growth pattern. The serial ultrasound follow-up of these at-risk patients allows identifying these brain growth patterns early, which offers a window of opportunity for implementing earlier interventions.

Caffeine Restores Neuronal Damage and Inflammatory Response in a Model of Intraventricular Hemorrhage of the Preterm Newborn.

Germinal matrix-intraventricular hemorrhage (GM-IVH) is the most frequent intracranial hemorrhage in the preterm infant (PT). Long-term GM-IVH-associated sequelae include cerebral palsy, sensory and motor impairment, learning disabilities, or neuropsychiatric disorders. The societal and health burden associated with GM-IVH is worsened by the fact that there is no successful treatment to limit or reduce brain damage and neurodevelopment disabilities. Caffeine (Caf) is a methylxanthine that binds to adenosine receptors, regularly used to treat the apnea of prematurity. While previous studies support the beneficial effects at the brain level of Caf in PT, there are no studies that specifically focus on the role of Caf in GM-IVH. Therefore, to further understand the role of Caf in GM-IVH, we have analyzed two doses of Caf (10 and 20 mg/kg) in a murine model of the disease. We have analyzed the short (P14) and long (P70) effects of the treatment on brain atrophy and neuron wellbeing, including density, curvature, and phospho-tau/total tau ratio. We have analyzed proliferation and neurogenesis, as well as microglia and hemorrhage burdens. We have also assessed the long-term effects of Caf treatment at cognitive level. To induce GM-IVH, we have administered intraventricular collagenase to P7 CD1 mice and have analyzed these animals in the short (P14) and long (P70) term. Caf showed a general neuroprotective effect in our model of GM-IVH of the PT. In our study, Caf administration diminishes brain atrophy and ventricle enlargement. Likewise, Caf limits neuronal damage, including neurite curvature and tau phosphorylation. It also contributes to maintaining neurogenesis in the subventricular zone, a neurogenic niche that is severely affected after GM-IVH. Furthermore, Caf ameliorates small vessel bleeding and inflammation in both the cortex and the subventricular zone. Observed mitigation of brain pathological features commonly associated with GM-IVH also results in a significant improvement of learning and memory abilities in the long term. Altogether, our data support the promising effects of Caf to reduce central nervous system complications associated with GM-IVH.

Lung ultrasound score has better diagnostic ability than NT-proBNP to predict moderate-severe bronchopulmonary dysplasia.

The N-terminal end of B-type natriuretic peptide (NT-proBNP) and lung ultrasound (LUS) score have been proven to be adequate early biomarkers of bronchopulmonary dysplasia (BPD) in preterm infants. Our aim was to study if the predictive capacity of each one is increased by analyzing them together. We included infants born before 32 weeks with NT-proBNP and LUS scores on the first day of life (DOL) and on the 3rd, 7th, and 14th DOL and compared the diagnostic ability for moderate-severe BPD (msBPD) of each biomarker and in combination. We also compared them with a multivariate model of msBPD using only clinical variables. The sample size was 133 patients, and twenty-seven (20%) developed msBPD. The LUS score on the 7th DOL had better performance than NT-proBNP at the same moment: area under the receiver operating characteristic curve (AUC) 0.83 (0.75-0.89) versus 0.66 (0.56-0.75), p = 0.003, without differences in the rest of the times studied. These values did not increase when using the combination of both. A multivariate regression model that included only clinical variables (birth weight and invasive mechanical ventilation (IMV) at the 7th DOL) predicted msBPD with the same AUC as after the addition of any of these biomarkers, neither together. CONCLUSION: The LUS score is a better predictor of msBPD on the 7th DOL than NT-proBNP in preterm infants born before 32 weeks, although they have similar diagnostic accuracy on the 1st, 3rd, and 14th DOL. Neither of them, nor together, have a better AUC for msBPD than a clinical model with birthweight and the need for IMV at the 7th DOL. WHAT IS KNOWN: • NT-proBNP and LUS score are early predictors of moderate-severe bronchopulmonary dysplasia (msBPD). WHAT IS NEW: • The combination of both NT-proBNP and LUS score does not increase the predictive ability of each separately.

Alteraciones en resonancia magnética asociadas a tratamiento con vigabatrina / Magnetic resonance imaging abnormalities associated with vigabatrin therapy

No disponible

Neonatal arterial stroke location is associated with outcome at 2 years: a voxel-based lesion-symptom mapping study.

OBJECTIVE: In contrast to motor impairments, the association between lesion location and cognitive or language deficits in patients with neonatal arterial ischaemic stroke remains largely unknown. We conducted a voxel-based lesion-symptom mapping cross-sectional study aiming to reveal neonatal arterial stroke location correlates of language, motor and cognitive outcomes at 2 years of age. DESIGN: Prospective observational multicentre study. SETTING: Six paediatric university hospitals in Spain. PARTICIPANTS: We included 53 patients who had a neonatal arterial ischaemic stroke with neonatal MRI and who were followed up till 2 years of age. MAIN OUTCOME MEASURES: We analysed five dichotomous clinical variables: speech therapy (defined as the need for speech therapy as established by therapists), gross motor function impairment, and the language, motor and cognitive Bayley scales. All the analyses were controlled for total lesion volume. RESULTS: We found that three of the clinical variables analysed significantly correlated with neonatal stroke location. Speech therapy was associated with lesions located mainly at the left supramarginal gyrus (p=0.007), gross motor function impairment correlated with lesions at the left external capsule (p=0.044) and cognitive impairment was associated with frontal lesions, particularly located at the left inferior and middle frontal gyri (p=0.012). CONCLUSIONS: The identification of these susceptible brain areas will allow for more precise prediction of neurological impairments on the basis of neonatal brain MRI.

Ultrasonographic Estimation of Total Brain Volume: 3D Reliability and 2D Estimation. Enabling Routine Estimation During NICU Admission in the Preterm Infant.

Objectives: The aim of this study is to explore if manually segmented total brain volume (TBV) from 3D ultrasonography (US) is comparable to TBV estimated by magnetic resonance imaging (MRI). We then wanted to test 2D based TBV estimation obtained through three linear axes which would enable monitoring brain growth in the preterm infant during admission. Methods: We included very low birth weight preterm infants admitted to our neonatal intensive care unit (NICU) with normal neuroimaging findings. We measured biparietal diameter, anteroposterior axis, vertical axis from US and MRI and TBV from both MRI and 3D US. We calculated intra- and interobserver agreement within and between techniques using the intraclass correlation coefficient and Bland-Altman methodology. We then developed a multilevel prediction model of TBV based on linear measurements from both US and MRI, compared them and explored how they changed with increasing age. The multilevel prediction model for TBV from linear measures was tested for internal and external validity and we developed a reference table for ease of prediction of TBV. Results: We used measurements obtained from 426 US and 93 MRI scans from 118 patients. We found good intra- and interobserver agreement for all the measurements. US measurements were reliable when compared to MRI, including TBV which achieved excellent agreement with that of MRI [ICC of 0.98 (95% CI 0.96-0.99)]. TBV estimated through 2D measurements of biparietal diameter, anteroposterior axis, and vertical axis was comparable among both techniques. We estimated the population 95% confidence interval for the mean values of biparietal diameter, anteroposterior axis, vertical axis, and total brain volume by post-menstrual age. A TBV prediction table based on the three axes is proposed to enable easy implementation of TBV estimation in routine 2D US during admission in the NICU. Conclusions: US measurements of biparietal diameter, vertical axis, and anteroposterior axis are reliable. TBV segmented through 3D US is comparable to MRI estimated TBV. 2D US accurate estimation of TBV is possible through biparietal diameter, vertical, and anteroposterior axes.

Automatic segmentation of ventricular volume by 3D ultrasonography in post haemorrhagic ventricular dilatation among preterm infants.

To train, evaluate, and validate the application of a deep learning framework in three-dimensional ultrasound (3D US) for the automatic segmentation of ventricular volume in preterm infants with post haemorrhagic ventricular dilatation (PHVD). We trained a 2D convolutional neural network (CNN) for automatic segmentation ventricular volume from 3D US of preterm infants with PHVD. The method was validated with the Dice similarity coefficient (DSC) and the intra-class coefficient (ICC) compared to manual segmentation. The mean birth weight of the included patients was 1233.1 g (SD 309.4) and mean gestational age was 28.1 weeks (SD 1.6). A total of 152 serial 3D US from 10 preterm infants with PHVD were analysed. 230 ventricles were manually segmented. Of these, 108 were used for training a 2D CNN and 122 for validating the methodology for automatic segmentation. The global agreement for manual versus automated measures in the validation data (n = 122) was excellent with an ICC of 0.944 (0.874-0.971). The Dice similarity coefficient was 0.8 (± 0.01). 3D US based ventricular volume estimation through an automatic segmentation software developed through deep learning improves the accuracy and reduces the processing time needed for manual segmentation using VOCAL. 3D US should be considered a promising tool to help deepen our current understanding of the complex evolution of PHVD.

Liraglutide Reduces Vascular Damage, Neuronal Loss, and Cognitive Impairment in a Mixed Murine Model of Alzheimer's Disease and Type 2 Diabetes.

Alzheimer's disease is the most common form of dementia, and epidemiological studies support that type 2 diabetes (T2D) is a major contributor. The relationship between both diseases and the fact that Alzheimer's disease (AD) does not have a successful treatment support the study on antidiabetic drugs limiting or slowing down brain complications in AD. Among these, liraglutide (LRGT), a glucagon-like peptide-1 agonist, is currently being tested in patients with AD in the Evaluating Liraglutide in Alzheimer's Disease (ELAD) clinical trial. However, the effects of LRGT on brain pathology when AD and T2D coexist have not been assessed. We have administered LRGT (500 µg/kg/day) to a mixed murine model of AD and T2D (APP/PS1xdb/db mice) for 20 weeks. We have evaluated metabolic parameters as well as the effects of LRGT on learning and memory. Postmortem analysis included assessment of brain amyloid-ß and tau pathologies, microglia activation, spontaneous bleeding and neuronal loss, as well as insulin and insulin-like growth factor 1 receptors. LRGT treatment reduced glucose levels in diabetic mice (db/db and APP/PS1xdb/db) after 4 weeks of treatment. LRGT also helped to maintain insulin levels after 8 weeks of treatment. While we did not detect any effects on cortical insulin or insulin-like growth factor 1 receptor m-RNA levels, LRGT significantly reduced brain atrophy in the db/db and APP/PS1xdb/db mice. LRGT treatment also rescued neuron density in the APP/PS1xdb/db mice in the proximity (p = 0.008) far from amyloid plaques (p < 0.001). LRGT reduced amyloid plaque burden in the APP/PS1 animals (p < 0.001), as well as Aß aggregates levels (p = 0.046), and tau hyperphosphorylation (p = 0.009) in the APP/PS1xdb/db mice. Spontaneous bleeding was also ameliorated in the APP/PS1xdb/db animals (p = 0.012), and microglia burden was reduced in the proximity of amyloid plaques in the APP/PS1 and APP/PS1xdb/db mice (p < 0.001), while microglia was reduced in areas far from amyloid plaques in the db/db and APP/PS1xdb/db mice (p < 0.001). This overall improvement helped to rescue cognitive impairment in AD-T2D mice in the new object discrimination test (p < 0.001) and Morris water maze (p < 0.001). Altogether, our data support the role of LRGT in reduction of associated brain complications when T2D and AD occur simultaneously, as regularly observed in the clinical arena.

Germinal Matrix-Intraventricular Hemorrhage of the Preterm Newborn and Preclinical Models: Inflammatory Considerations.

The germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most important complications of the preterm newborn. Since these children are born at a critical time in brain development, they can develop short and long term neurological, sensory, cognitive and motor disabilities depending on the severity of the GM-IVH. In addition, hemorrhage triggers a microglia-mediated inflammatory response that damages the tissue adjacent to the injury. Nevertheless, a neuroprotective and neuroreparative role of the microglia has also been described, suggesting that neonatal microglia may have unique functions. While the implication of the inflammatory process in GM-IVH is well established, the difficulty to access a very delicate population has lead to the development of animal models that resemble the pathological features of GM-IVH. Genetically modified models and lesions induced by local administration of glycerol, collagenase or blood have been used to study associated inflammatory mechanisms as well as therapeutic targets. In the present study we review the GM-IVH complications, with special interest in inflammatory response and the role of microglia, both in patients and animal models, and we analyze specific proteins and cytokines that are currently under study as feasible predictors of GM-IVH evolution and prognosis.