The Global Impact of the Intrauterine Experience on Neuropsychlogical Health Prenatal Fetal Brain Remodeling

Transcription

1 The Global Impact of the Intrauterine Experience on Neuropsychlogical Health Prenatal Fetal Brain Remodeling Eduard Gratacos Barcelona Center Maternal-Fetal and Neonatal Medicine Hospitals Clinic and Sant Joan de Deu - University of Barcelona

2 Guillem was born at Maternitat (Hospital Clínic) with a diagnosis of mild fetal growth restriction. You even offered us to participate in a study of brain MRI. Now he is almost 6 and he is suffering problems with learning, and irritable mood with intolerance to frustration Do you think these problems were caused by the problem of fetal growth restriction? Do you think this might cause further problems? We remain awaiting your news,

3 Prenatal conditions and neurodevelopment Evidence and Biomarkers Potential interventions

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5 Migration Programmed cell death Myelination Axonal/Dendrite arborization Synaptogenesis exposure Brain reorganiza+on (+/- injury) Fetal programming

6 Prematurity Exposure Infection Fetal growth restriction Genetics Neurocognitive disorders/learning disabilities Overall 10% Estimated 2/3 of prenatal origin Non-specific disorders 5-8% Attention Deficit Hyperactivity Disorder 2-5% Autism Spectrum Disorder 0.5-1%

7 IDENTIFICATION OF RISK 4P medicine Predictive Preventive Personalized Participatory INDIVIDUAL BIOMARKERS INTERVENTION BIRTH WINDOW OF OPPORTUNITY Fetus Child Programming - Remodelling Problem evident

8 Prenatal conditions and neurodevelopment Evidence and Biomarkers Potential interventions

9 Fetal growth restriction (and other disorders associated with disease or abnormal environment) Adaptation = Epigenetics = Permanent programming /remodeling Brain reorganization Cardiovascular remodelling Metabolic programming

10 Dichorionic Twins. Born 34 weeks Twin 1: 1950 g (p45) Twin 2: 1200 g (p1). Normal Doppler * * * Bayley Score cognitive language motor socio-emot adaptive behavior Satchev, 2012 Figueras Baschat 2009, 2011 Vohr 2004 Geva

11 EFFECTS OF IUGR ON THE FETAL BRAIN MICROSTRUCTURE METABOLISM CORTICAL DEVELOPMENT CONNECTIVITY

12 Normal acoustic signature WMD acoustic signature WMD Score Normal WMD Ultrasound texture analysis (feature extraction + machine learning) J Ultrasound Med 2011 Fetal Diagn Ther 2012 Am J Obstet Gynecol 2012

13 IUGR IS ASSOCIATED WITH DIFFERENCES IN CORPUS CALLOSUM AND CORTICAL DEVELOPMENT Composite score of insular depth and parieto-occipital fissure CC length and total area PLoSOne 2012, UOG 2013, AJOG 2013

14 NEURO&METABOLOME,PROJECT, BRAIN METABOLISM AND MICROSTRUCTURE MRS:MAGNETIC,RESONANCE, SPECTROSCOPY, NAA Myo Ino Cho Metabolites and neural function-maturation: -N-acetyl-aspartate (NAA): Neuronal marker. -Choline (Cho): Myelination and cell membrane turnover -Creatine (Cre): Cellular energy -Myo-Inositol (Myo-Ino): Glial marker. Osmoregulation Sanz 2010 Preterm IUGR Van Vliet, PLoS 2012 Term IUGR AJOG 2014 AJOG submi/ed

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16 Neuroimage 2012 PLoS One 2012

17 IUGR and connectivity of specific brain tracts Background: Children with ajenkon-deficit disorders have impaired corkco-striato-thalamic conneckvity. normal IUGR Cortico-striato-thalamic right ipsilateral connectivity in infants with with fetal growth restriction. (preliminary results)

18 24 IUGR 27 controls DTI MRI 1 year old Specific correlation with function at two years of age Eixarch E, AJOG Jun;214(6):725.e1-9

19 Dendritic spines 4 animals/group dendrites x hemisphere Regression analysis, adjusted by gender

20 Perineuronal nets n= 6 cnt / 6 IUGR * histology results CONTROL Total pnn/µm IUGR Regression analysis, adjusted by gender Next step: assessment in therapy groups & neonatal period

21 Brain connectivity differences in FGR persist until adolescence in experimental models Figure 5. Ratio of fibers involved in the anxiety (lft) or memory (right) circuit over the total amount of fibers. (A) adjusted for gender PLoS One 2011, 2012, Neuroimage 2014

22 in collaboration with UPF (Deco G and cols.)

23 Prenatal conditions and neurodevelopment Evidence and Biomarkers Potential interventions

24 BIOLOGIC PROGRAMMING AND AGE IMPACT OF ENVIRONMENT OPPORTUNITY FOR CORRECTION Fetus Child Young Mature Old

25 Fetal growth restriction (and other disorders associated with disease or abnormal environment) Adaptation = Epigenetics = Permanent programming /remodeling Brain reorganization Cardiovascular remodelling Metabolic programming

26 IDENTIFICATION OF THE PROBLEM: RESTRICTION (not just smallness) INDIVIDUAL BIOMARKERS INTERVENTION BIRTH WINDOW OF OPPORTUNITY Fetus Child Adult Programming / Organ remodelling Problem evident

27 SUBPROGRAM 1 Brain programming in IUGR WP 3. New therapeutic approaches to reduce brain programming: preclinical studies To evaluate structural and functional abnormalities in the animal model of IUGR. To study the neuroprotective effect of env. enrichment, lactoferrin and omega 3-fatty acids Prenatal strategies Postnatal strategies prenatal insult fetal brain programming postnatal consequences +1P +70P IUGR Induction +1P & +70p +1P +70P No treatment imaging biomarkers MRI texture analysis histology & immunochemistry Environment Enrichment DHA structure function Lactoferrin

28 WP 3. New therapeutic approaches on prenatal brain remodeling: preclinical studies Postnatal: Environmental enrichment memory global efficiency of brain networks HPC dendritic spine * * * * * * Ctol nt-iugr t-iugr Ctol nt-iugr t-iugr Ctol nt-iugr t-iugr

29 WP 3. New therapeutic approaches prenatal brain remodeling: preclinical studies Perinatal strategies: Lactoferrin & Omega-3 * * +70P +1P mortality memory * * brain networks HPC dendritic spine * * * * n.s

30 Illa (unpublished)

31 FGR and other prenatal conditions represent an opportunity to improve early neurodevelopment. Need to define mechanistic pathways. Biomarkers useful for research but not in clinical practice. Need for clinical trials with the challenge of defining well the condition and the intervention. Future interventions focused at the public health level (high prevalence + lack of specific biomarkers).

32 Fetal Programming / Remodeling Impact of prenatal events on the brain Eduard Gratacos Barcelona Center Maternal-Fetal and Neonatal Medicine Hospitals Clinic and Sant Joan de Deu - University of Barcelona

33 Congenital Heart Disease MRI-Spectroscopy: NAA By CHD type By MCA n=58 cases and 56 controls Masoller et al. 2016