Infant Neuromotor Development and Neuropsychiatric Problems Modern Epidemiological approaches

__Background:__ This thesis focuses on the role of infant neuromotor development in relation to neuropsychiatric problems. I performed genetic studies to further our understanding of the association between neuromotor development in infancy and behavioral problems in childhood. Methods: Studies described in this thesis were performed in Generation R, a large prospective population-based cohort in Rotterdam, the Netherlands. In a large ample of children at age 9-20 weeks, 15 research assistants assessed neuromotor development (tone, responses, senses and other observations) using Touwen instrument. Parents reported on their behavior during childhood and cognitive abilities were observed at age 6 years. __Objectives:__ The aims of this thesis were 1) to study the associations between neuromotor development during infancy and childhood behavior and cognitive functioning, 2) to examine the extend to which genetic susceptibility for psychiatric disorders influences neuromotor development 3) to understand the role of infant neuromotor development in the association of genetic susceptibility for psychiatric disorders with behavioral outcomes during childhood. __Results:__ I showed that infant neuromotor development is associated with shifting and cold, but not hot executive functioning, as well as with autistic symptoms. I further found that infant neuromotor development (low muscle tone and senses) predicts internalizing, but not externalizing symptoms during childhood. Problems in shifting partly mediated association between low muscle tone and later internalizing symptoms. Furthermore, a higher genetic risk for schizophrenia and a lower genetic risk for bipolar disorder was associated with non-optimal overall neuromotor development during infancy. I also found that the genetic risk for autism spectrum disorder (ASD) predicts non-optimal neuromotor development and in particular low muscle tone, while the genetic risk for attention-deficit/hyperactivity disorder (ADHD) predicts non-optimal senses and other observations in boys. Infant neuromotor development mediates the association of genetic risk for ASD and ADHD with autistic symptoms. In particular, low muscle tone mediates the association of genetic risk for ASD with autistic symptoms, while senses and other observations mediate association of genetic risk for ASD and ADHD with autistic symptoms. __Conclusion:__ Early identification of non-optimal neuromotor development in infants with a high genetic risk, followed by early intervention, could potentially reduce autistic symptoms in children

Prevention and Management of Type 2 Diabetes and Metabolic Syndrome in the Time of COVID-19: Should We Add a Cup of Coffee?

Recent evidence shows that COVID-19 patients with existing metabolic disorders, such as diabetes and metabolic syndrome, are exposed to a high risk of morbidity and mortality. At the same time, in order to manage the pandemic, the health authorities around the world are advising people to stay at home. This results in decreased physical activity and an increased consumption of an unhealthy diet, which often leads to an increase in body weight, risk for diabetes, insulin resistance, and metabolic syndrome, and thus, paradoxically, to a high risk of morbidity and mortality due to COVID-19 complications. Here we summarize the evidence demonstrating that the promotion of a healthy life style, including physical activity and a dietary intake of natural polyphenols present in coffee and tea, has the potential to improve the prevention and management of insulin resistance and diabetes in the time of COVID-19 pandemic. Particularly, it would be pertinent to evaluate further the potential positive effects of coffee beverages, rich in natural polyphenols, as an adjuvant therapy for COVID-19, which appear not to be studied sufficiently

DNA methylation at birth and fine motor ability in childhood: an epigenome-wide association study with replication

DNA methylation; Cognitive function; Cord bloodMetilació de l'ADN; Funció cognitiva; Sang de cordóMetilación del ADN; Función cognitiva; Sangre de cordónLower fine motor performance in childhood has been associated with poorer cognitive development and neurodevelopmental conditions such as autism spectrum disorder, yet, biological underpinnings remain unclear. DNA methylation (DNAm), an essential process for healthy neurodevelopment, is a key molecular system of interest. In this study, we conducted the first epigenome-wide association study of neonatal DNAm with childhood fine motor ability and further examined the replicability of epigenetic markers in an independent cohort. The discovery study was embedded in Generation R, a large population-based prospective cohort, including a subsample of 924 ~ 1026 European-ancestry singletons with available data on DNAm in cord blood and fine motor ability at a mean (SD) age of 9.8 (0.4) years. Fine motor ability was measured using a finger-tapping test (3 subtests including left-, right-hand and bimanual), one of the most frequently used neuropsychological instruments of fine motor function. The replication study comprised 326 children with a mean (SD) age of 6.8 (0.4) years from an independent cohort, the INfancia Medio Ambiente (INMA) study. Four CpG sites at birth were prospectively associated with childhood fine motor ability after genome-wide correction. Of these, one CpG (cg07783800 in GNG4) was replicated in INMA, showing that lower levels of methylation at this site were associated with lower fine motor performance in both cohorts. GNG4 is highly expressed in the brain and has been implicated in cognitive decline. Our findings support a prospective, reproducible association between DNAm at birth and fine motor ability in childhood, pointing to GNG4 methylation at birth as a potential biomarker of fine motor ability.The EWAS data was funded by a grant from the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060-810), funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and a grant from the National Institute of Child and Human Development (R01HD068437). HT was supported by a grant of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (NWO grant No. 024.001.003, Consortium on Individual Development). FS was supported by a Royal Netherlands Academy of Science and Art (KNAW) Van Leersum fellowship. ML is supported by the scholarship from the China Scholarship Council (201706990036). CC is supported by the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements No 101039672 (TEMPO) and No 848158 (EarlyCause). This project received funding from the European Union’s Horizon 2020 research and innovation programme (733206, LifeCycle).The epigenetic studies in INMA were mainly funded by grants from Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041, CP18/00018), Spanish Ministry of Health (FIS-PI04/1436, FIS-PI08/1151 including FEDER funds, FIS-PI11/00610, FIS-FEDER-PI06/0867, FIS-FEDER-PI03-1615) Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació La marató de TV3 (090430), EU Commission (261357-MeDALL: Mechanisms of the Development of ALLergy), and European Research Council (268479-BREATHE: BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn)

Exploratory genetic analysis in children with autism spectrum disorder and other developmental disorders using whole exome sequencing

Developmental disorders (DDs), such as autism spectrum disorder (ASD), incorporate various conditions; once identified, further diagnostics are necessary to specify their type and severity. The aim of this exploratory study was to identify genetic variants that can help differentiate ASD early from other DDs. We selected 36 children (mean age 60.1 months) with DDs using Developmental Behavioral Scales (DBS) through "EDUS-Education for All", an organization providing services for children with developmental disorders in Bosnia and Herzegovina. We further rated children's autistic traits with the preschool version of the Childhood Autism Rating Scale, second edition (CARS-II). We defined ASD if scores were &gt;25.5 and other DDs if scores were &lt;25.5. Diagnosis of ASD and DD were independently confirmed by child psychiatrists. Whole exome sequencing (WES) was performed by Veritas Genetics, USA, using Illumina NovaSeq 6000 (Illumina Inc., San Diego, CA, USA) next-generation sequencing (NGS) apparatus. We tested genetic association by applying SKAT-O, which optimally combines the standard Sequence Kernel Association Test (SKAT) and burden tests to identify rare variants associated with complex traits in samples of limited power. The analysis yielded seven genes (DSE, COL10A1, DLK2, CSMD1, FAM47E, PPIA, PYDC2) to potentially differentiate observed phenotypic characteristics between our cohort participants with ASD and other DDs. Our exploratory study in a small sample of participants with ASD and other DDs contributed to gene discovery in differentiating ASD from DDs. A replication study is needed in a larger sample to confirm our results.</p

Effects of combined treatment of probiotics and metformin in management of type 2 diabetes:A systematic review and meta-analysis

Background: Lifestyle changes and dietary intervention, including the use of probiotics, can modulate dysbiosis of gut microbiome and contribute to the management of type 2 diabetes mellitus (T2DM). This systematic review and meta-analysis aim to assess the efficacy of metformin plus probiotics versus metformin alone on outcomes in patients with T2DM. Methods: We searched MEDLINE and EMBASE from inception to February 2023 to identify all randomized controlled trials (RCTs), which compared the use of metformin plus probiotics versus metformin alone in adult patients with T2DM. Data were summarized as mean differences (MD) with 95 % confidence interval (CI) and pooled under the random effects model. Findings: Fourteen RCTs (17 comparisons, 1009 patients) were included in this systematic review. Pooled results show a significant decrease in fasting glucose (FG) (MD = −0.64, 95 % CI = −1.06, −0.22) and HbA1c (MD = −0.29, 95 % CI = −0.47, −0.10) levels in patients with T2DM treated with metformin plus probiotics versus metformin alone. The addition of probiotics to metformin resulted in lower odds of gastrointestinal adverse events (Odds ratio = 0.18, 95 % CI = 0.09, 0.3.8; I2 = 0 %). Conclusions: The addition of probiotics to metformin therapy is associated with improvement in T2DM outcomes. However, high-quality and adequately reported RCTs are needed in the future to confirm our findings.</p

PPAR agonists as add-on treatment with metformin in management of type 2 diabetes:a systematic review and meta-analysis

The combination of metformin and the peroxisome proliferator-activated receptors (PPAR) agonists offers a promising avenue for managing type 2 diabetes (T2D) through their potential complementary mechanisms of action. The results from randomized controlled trials (RCT) assessing the efficacy of PPAR agonists plus metformin versus metformin alone in T2D are inconsistent, which prompted the conduct of the systematic review and meta-analysis. We searched MEDLINE and EMBASE from inception (1966) to March 2023 to identify all RCTs comparing any PPAR agonists plus metformin versus metformin alone in T2D. Categorical variables were summarized as relative risk along with 95% confidence interval (CI). Twenty RCTs enrolling a total of 6058 patients met the inclusion criteria. The certainty of evidence ranged from moderate to very low. Pooled results show that using PPAR agonist plus metformin, as compared to metformin alone, results in lower concentrations of fasting glucose [MD = - 22.07 mg/dl (95% CI - 27.17, - 16.97), HbA1c [MD = - 0.53% (95% CI - 0.67, - 0.38)], HOMA-IR [MD = - 1.26 (95% CI - 2.16, - 0.37)], and fasting insulin [MD = - 19.83 pmol/L (95% CI - 29.54, - 10.13)] without significant increase in any adverse events. Thus, synthesized evidence from RCTs demonstrates the beneficial effects of PPAR agonist add-on treatment versus metformin alone in T2D patients. In particular, novel dual PPARα/γ agonist (tesaglitazar) demonstrate efficacy in improving glycaemic and lipid concentrations, so further RCTs should be performed to elucidate the long-term outcomes and safety profile of these novel combined and personalized therapeutic strategies in the management of T2D.PROSPERO registration no. CRD42023412603.</p

Exploratory genetic analysis in children with autism spectrum disorder and other developmental disorders using whole exome sequencing

Developmental disorders (DDs), such as autism spectrum disorder (ASD), incorporate various conditions; once identified, further diagnostics are necessary to specify their type and severity. The aim of this exploratory study was to identify genetic variants that can help differentiate ASD early from other DDs. We selected 36 children (mean age 60.1 months) with DDs using Developmental Behavioral Scales (DBS) through “EDUS-Education for All”, an organization providing services for children with developmental disorders in Bosnia and Herzegovina. We further rated children's autistic traits with the preschool version of the Childhood Autism Rating Scale, second edition (CARS-II). We defined ASD if scores were >25.5 and other DDs if scores were <25.5. Diagnosis of ASD and DD were independently confirmed by child psychiatrists. Whole exome sequencing (WES) was performed by Veritas Genetics, USA, using Illumina NovaSeq 6000 (Illumina Inc., San Diego, CA, USA) next-generation sequencing (NGS) apparatus. We tested genetic association by applying SKAT-O, which optimally combines the standard Sequence Kernel Association Test (SKAT) and burden tests to identify rare variants associated with complex traits in samples of limited power. The analysis yielded seven genes (DSE, COL10A1, DLK2, CSMD1, FAM47E, PPIA, PYDC2) to potentially differentiate observed phenotypic characteristics between our cohort participants with ASD and other DDs. Our exploratory study in a small sample of participants with ASD and other DDs contributed to gene discovery in differentiating ASD from DDs. A replication study is needed in a larger sample to confirm our results

Effects of Pre- and Postnatal Early-Life Stress on Internalizing, Adiposity, and Their Comorbidity

Objective: Depression and obesity are 2 highly prevalent and often comorbid conditions. Exposure to early-life stress (ELS) has been associated with both depression and obesity in adulthood, as well as their preclinical manifestations during development. However, it remains unclear whether (1) associations differ depending on the timing of stress exposure (prenatal vs postnatal), and whether (2) ELS is a shared risk factor underlying the comorbidity between the 2 conditions. Method: Leveraging data from 2 large population-based birth cohorts (ALSPAC: n = 8,428 [52% male participants]; Generation R: n = 4,268 [48% male participants]), we constructed comprehensive cumulative measures of prenatal (in utero) and postnatal (from birth to 10 years) ELS. At age 13.5 years, we assessed the following: internalizing symptoms (using maternal reports); fat mass percentage (using dual-energy X-ray absorptiometry); and their comorbidity, defined as the co-occurrence of high internalizing and high adiposity. Results: Both prenatal (total effect [95% CI] = 0.20 [0.16; 0.22]) and postnatal stress (β [95%CI] = 0.22 [0.17; 0.25]) were associated with higher internalizing symptoms, with evidence of a more prominent role of postnatal stress. A weaker association (driven primarily by prenatal stress) was observed between stress and adiposity (prenatal: 0.07 [0.05; 0.09]; postnatal: 0.04 [0.01; 0.07]). Both prenatal (odds ratio [95%CI] = 1.70 [1.47; 1.97]) and postnatal (1.87 [1.61; 2.17]) stress were associated with an increased risk of developing comorbidity. Conclusion: We found evidence of timing and shared causal effects of ELS on psycho-cardiometabolic health in adolescence; however, future research is warranted to clarify how these associations may unfold over time. Diversity &amp; Inclusion Statement: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group.</p