Aldo Córdova-Palomera

Glucocorticoid receptor gene (NR3C1) methylation processes as mediators of early adversity in stress-related disorders causality: A critical review.

Early life stress (ELS) is a known risk factor for suffering psychopathology in adulthood. The hypothalamic-pituitary-adrenal (HPA) axis has been described to be deregulated in both individuals who experienced early psychosocial stress and in patients with a wide range of psychiatric disorders. The NR3C1 gene codes for the glucocorticoid receptor, a key element involved in several steps of HPA axis modulation. In this review, we gather existing evidence linking NR3C1 methylation pattern with either ELS or psychopathology. We summarize that several types of ELS have been frequently associated with NR3C1 hypermethylation whereas hypomethylation has been continuously found to be associated with post-traumatic stress disorder. In light of the reported findings, the main concerns of ongoing research in this field are the lack of methodological consensus and selection of CpG sites. Further studies should target individual CpG site methylation assessment focusing in biologically relevant areas such as transcription factor binding regions whereas widening the examined sequence in order to include all non-coding first exons of the NR3C1 gene in the analysis.

Maternal psychosocial stress during pregnancy alters the epigenetic signature of the glucocorticoid receptor gene promoter in their offspring: a meta-analysis

Prenatal stress has been widely associated with a number of short- and long-term pathological outcomes. Epigenetic mechanisms are thought to partially mediate these environmental insults into the fetal physiology. One of the main targets of developmental programming is the hypothalamic-pituitary-adrenal (HPA) axis as it is the main regulator of the stress response. Accordingly, an increasing number of researchers have recently focused on the putative association between DNA methylation at the glucocorticoid receptor gene (NR3C1) and prenatal stress, among other types of psychosocial stress. The current study aims to systematically review and meta-analyze the existing evidence linking several forms of prenatal stress with DNA methylation at the region 1F of the NR3C1 gene. The inclusion of relevant articles allowed combining empirical evidence from 977 individuals by meta-analytic techniques, whose methylation assessments showed overlap across 5 consecutive CpG sites (GRCh37/hg19 chr5:142,783,607-142,783,639). From this information, methylation levels at CpG site 36 displayed a significant correlation to prenatal stress (r = 0.14, 95% CI: 0.05–0.23, P = 0.002). This result supports the proposed association between a specific CpG site located at the NR3C1 promoter and prenatal stress. Several confounders, such as gender, methylation at other glucocorticoid-related genes, and adjustment for pharmacological treatments during pregnancy, should be taken into account in further studies.

Disrupted global metastability and static and dynamic brain connectivity across individuals in the Alzheimer’s disease continuum

As findings on the neuropathological and behavioral components of Alzheimer’s disease (AD) continue to accrue, converging evidence suggests that macroscale brain functional disruptions may mediate their association. Recent developments on theoretical neuroscience indicate that instantaneous patterns of brain connectivity and metastability may be a key mechanism in neural communication underlying cognitive performance. However, the potential significance of these patterns across the AD spectrum remains virtually unexplored. We assessed the clinical sensitivity of static and dynamic functional brain disruptions across the AD spectrum using resting-state fMRI in a sample consisting of AD patients (n = 80) and subjects with either mild (n = 44) or subjective (n = 26) cognitive impairment (MCI, SCI). Spatial maps constituting the nodes in the functional brain network and their associated time-series were estimated using spatial group independent component analysis and dual regression, and whole-brain oscillatory activity was analyzed both globally (metastability) and locally (static and dynamic connectivity). Instantaneous phase metrics showed functional coupling alterations in AD compared to MCI and SCI, both static (putamen, dorsal and default-mode) and dynamic (temporal, frontal-superior and default-mode), along with decreased global metastability. The results suggest that brains of AD patients display altered oscillatory patterns, in agreement with theoretical premises on cognitive dynamics.

Consistent Functional Connectivity Alterations in Schizophrenia Spectrum Disorder: A Multisite Study

Schizophrenia (SZ) is a severe mental illness with high heritability and complex etiology. Mounting evidence from neuroimaging has implicated disrupted brain network connectivity in the pathophysiology. However, previous findings are inconsistent, likely due to a combination of methodological and clinical variability and relatively small sample sizes. Few studies have used a data-driven approach for characterizing pathological interactions between regions in the whole brain and evaluated the generalizability across independent samples. To overcome this issue, we collected resting-state functional magnetic resonance imaging data from 3 independent samples (1 from Norway and 2 from Sweden) consisting of 182 persons with a SZ spectrum diagnosis and 348 healthy controls. We used a whole-brain data-driven definition of network nodes and regularized partial correlations to evaluate and compare putatively direct brain network node interactions between groups. The clinical utility of the functional connectivity features and the generalizability of effects across samples were evaluated by training and testing multivariate classifiers in the independent samples using machine learning. Univariate analyses revealed 14 network edges with consistent reductions in functional connectivity encompassing frontal, somatomotor, visual, auditory, and subcortical brain nodes in patients with SZ. We found a high overall accuracy in classifying patients and controls (up to 80%) using independent training and test samples, strongly supporting the generalizability of connectivity alterations across different scanners and heterogeneous samples. Overall, our findings demonstrate robust reductions in functional connectivity in SZ spectrum disorders, indicating disrupted information flow in sensory, subcortical, and frontal brain regions.

Cerebellar volume and cerebellocerebral structural covariance in schizophrenia: a multisite mega-analysis of 983 patients and 1349 healthy controls

Although cerebellar involvement across a wide range of cognitive and neuropsychiatric phenotypes is increasingly being recognized, previous large-scale studies in schizophrenia (SZ) have primarily focused on supratentorial structures. Hence, the across-sample reproducibility, regional distribution, associations with cerebrocortical morphology and effect sizes of cerebellar relative to cerebral morphological differences in SZ are unknown. We addressed these questions in 983 patients with SZ spectrum disorders and 1349 healthy controls (HCs) from 14 international samples, using state-of-the-art image analysis pipelines optimized for both the cerebellum and the cerebrum. Results showed that total cerebellar grey matter volume was robustly reduced in SZ relative to HCs (Cohens’s d=−0.35), with the strongest effects in cerebellar regions showing functional connectivity with frontoparietal cortices (d=−0.40). Effect sizes for cerebellar volumes were similar to the most consistently reported cerebral structural changes in SZ (e.g., hippocampus volume and frontotemporal cortical thickness), and were highly consistent across samples. Within groups, we further observed positive correlations between cerebellar volume and cerebral cortical thickness in frontotemporal regions (i.e., overlapping with areas that also showed reductions in SZ). This cerebellocerebral structural covariance was strongest in SZ, suggesting common underlying disease processes jointly affecting the cerebellum and the cerebrum. Finally, cerebellar volume reduction in SZ was highly consistent across the included age span (16–66 years) and present already in the youngest patients, a finding that is more consistent with neurodevelopmental than neurodegenerative etiology. Taken together, these novel findings establish the cerebellum as a key node in the distributed brain networks underlying SZ.

Brain structural and clinical changes after first episode psychosis: Focus on cannabinoid receptor 1 polymorphisms

Cannabinoid receptor 1 (CNR1) gene polymorphisms have been associated with central and peripheral effects of cannabis and schizophrenia pathophysiology. Here, we have tested whether three CNR1 variants (rs1049353, rs1535255 and rs2023239) are associated with changes in brain volumes, body mass index (BMI) or psychopathological scores in a 3-year longitudinal study of 65 first-episode psychosis patients. The rs1049353 at-risk allele was significantly associated with a greater reduction of caudate volume, and the rs2023239 T/C polymorphism showed a significant decrease in thalamic volume after the 3-year period. For those who were not cannabis users, the rs1535255 and rs2023239 polymorphisms had effects in lateral ventricle (LV), and LV and white matter, respectively. The rs2023239 variant also was associated with significant improvements in positive and negative symptoms of schizophrenia. There was no significant effect of any of the variants on changes in BMI over the 3-year study. Finally, an interaction between all three polymorphisms was found involving evolution of positive symptoms. These findings suggest that the cannabinoid pathway is associated with schizophrenia evolution over time. However, further studies using larger cohorts are needed to confirm these results. If confirmed, the present findings could lead in subsequent investigations for identification of novel drug targets for improved treatment of patients suffering from schizophrenia.

Dissociable diffusion MRI patterns of white matter microstructure and connectivity in Alzheimer’s disease spectrum

Recent efforts using diffusion tensor imaging (DTI) have documented white matter (WM) alterations in Alzheimer’s disease (AD). The full potential of whole-brain DTI, however, has not been fully exploited as studies have focused on individual microstructural indices independently. In patients with AD (n = 79), mild (MCI, n = 55) and subjective (SCI, n = 30) cognitive impairment, we applied linked independent component analysis (LICA) to model inter-subject variability across five complementary DTI measures (fractional anisotropy (FA), axial/radial/mean diffusivity, diffusion tensor mode), two crossing fiber measures estimated using a multi-compartment crossing-fiber model reflecting the volume fraction of the dominant (f1) and non-dominant (f2) diffusion orientation, and finally, connectivity density obtained from full-brain probabilistic tractography. The LICA component explaining the largest data variance was highly sensitive to disease severity (AD < MCI < SCI) and revealed widespread coordinated decreases in FA and f1 with increases in all diffusivity measures in AD. Additionally, it reflected regional coordinated decreases and increases in f2, mode and connectivity density, implicating bidirectional alterations of crossing fibers in the fornix, uncinate fasciculi, corpus callosum and major sensorimotor pathways. LICA yielded improved diagnostic classification performance compared to univariate region-of-interest features. Our results document coordinated WM microstructural and connectivity alterations in line with disease severity across the AD continuum.

Polymorphic variation in the epigenetic gene DNMT3B modulates the environmental impact on cognitive ability: A twin study

BACKGROUND Though cognitive abilities in adulthood are largely influenced by individual genetic background, they have also been shown to be importantly influenced by environmental factors. Some of these influences are mediated by epigenetic mechanisms. Accordingly, polymorphic variants in the epigenetic gene DNMT3B have been linked to neurocognitive performance. Since monozygotic (MZ) twins may show larger or smaller intrapair phenotypic differences depending on whether their genetic background is more or less sensitive to environmental factors, a twin design was implemented to determine if particular polymorphisms in the DNMT3B gene may be linked to a better (worse) response to enriched (deprived) environmental factors. METHODS Applying the variability gene methodology in a sample of 54 healthy MZ twin pairs (108 individuals) with no lifetime history of psychopathology, two DNMT3B polymorphisms were analyzed in relation to their intrapair differences for either intellectual quotient (IQ) or working memory performance. RESULTS MZ twin pairs with the CC genotype for rs406193 SNP showed statistically significant larger intrapair differences in IQ than CT pairs. CONCLUSIONS Results suggest that DNMT3B polymorphisms may explain variability in the IQ response to either enriched or impoverished environmental conditions. Accordingly, the applied methodology is shown as a potentially valuable tool for determining genetic markers of cognitive plasticity. Further research is needed to confirm this specific result and to expand on other putative genetic markers of environmental sensitivity.

Birth Weight, Working Memory and Epigenetic Signatures in IGF2 and Related Genes: A MZ Twin Study

Neurodevelopmental disruptions caused by obstetric complications play a role in the etiology of several phenotypes associated with neuropsychiatric diseases and cognitive dysfunctions. Importantly, it has been noticed that epigenetic processes occurring early in life may mediate these associations. Here, DNA methylation signatures at IGF2 (insulin-like growth factor 2) and IGF2BP1-3 (IGF2-binding proteins 1-3) were examined in a sample consisting of 34 adult monozygotic (MZ) twins informative for obstetric complications and cognitive performance. Multivariate linear regression analysis of twin data was implemented to test for associations between methylation levels and both birth weight (BW) and adult working memory (WM) performance. Familial and unique environmental factors underlying these potential relationships were evaluated. A link was detected between DNA methylation levels of two CpG sites in the IGF2BP1 gene and both BW and adult WM performance. The BW-IGF2BP1 methylation association seemed due to non-shared environmental factors influencing BW, whereas the WM-IGF2BP1 methylation relationship seemed mediated by both genes and environment. Our data is in agreement with previous evidence indicating that DNA methylation status may be related to prenatal stress and later neurocognitive phenotypes. While former reports independently detected associations between DNA methylation and either BW or WM, current results suggest that these relationships are not confounded by each other.

Association of Heritable Cognitive Ability and Psychopathology With White Matter Properties in Children and Adolescents

Importance Many mental disorders emerge during adolescence, which may reflect a cost of the potential for brain plasticity offered during this period. Brain dysconnectivity has been proposed as a common factor across diagnostic categories. Objective To investigate the hypothesis that brain dysconnectivity is a transdiagnostic phenotype in adolescence with increased susceptibility and symptoms of psychiatric disease. Design, Setting, and Participants We investigated clinical symptoms as well as cognitive function in 6487 individuals aged 8 to 21 years from November 1, 2009, to November 30, 2011, in the Philadelphia Neurodevelopmental Cohort and analyzed diffusion magnetic resonance imaging brain scans for 748 of the participants. Main Outcomes and Measures Independent component analysis was used to derive dimensional psychopathology scores, and genome-wide complex trait analysis was used to estimate its heritability. Multimodal fusion simultaneously modeled contributions of the diffusion magnetic resonance imaging metrics fractional anisotropy, mean diffusivity, radial diffusivity, L1 (the principal diffusion tensor imaging eigen value), mode of anisotropy, as well as dominant and secondary fiber orientations, and structural connectivity density, and their association with general psychopathology and cognition. Results Machine learning with 10-fold cross-validation and permutation testing in 729 individuals (aged 8 to 22 years; mean [SD] age, 15.1 [3.3] years; 343 females [46%]) revealed significant association with general psychopathology levels (r = 0.24, P < .001) and cognition (r = 0.39, P < .001). A brain white matter pattern reflecting frontotemporal connectivity and crossing fibers in the uncinate fasciculus was the most associated feature for both traits. Univariate analysis across a range of clinical domains and cognitive test scores confirmed its transdiagnostic importance. Both the general psychopathology (16%; SE, 0.095; P = .05) and cognitive (18%; SE, 0.09; P = .01) factor were heritable and showed a negative genetic correlation. Conclusion and relevance Dimensional and heritable general cognitive and psychopathology factors are associated with specific patterns of white matter properties, suggesting that dysconnectivity is a transdiagnostic brain-based phenotype in individuals with increased susceptibility and symptoms of psychiatric disorders.