Iram Kazimi

Accelerated epigenetic aging and mitochondrial DNA copy number in bipolar disorder

Bipolar disorder (BD) has been previously associated with accelerated aging; yet, the mechanisms underlying this association are largely unknown. The epigenetic clock has been increasingly recognized as a valuable aging marker, although its association with other biological clocks in BD patients and high-risk subjects, such as telomere length and mitochondrial DNA (mtDNA) copy number, has never been investigated. We included 22 patients with BD I, 16 siblings of BD patients, and 20 healthy controls in this analysis. DNA was isolated from peripheral blood and interrogated for genome-wide DNA methylation, mtDNA copy number, and telomere length. DNA methylation age (DNAm age) and accelerated aging were calculated using the Horvath age estimation algorithm in blood and in postmortem brain from BD patients and nonpsychiatric controls using publicly available data. Older BD patients presented significantly accelerated epigenetic aging compared to controls, whereas no difference was detected among the younger subjects. Patients showed higher levels of mtDNA copy number, while no difference was found between controls and siblings. mtDNA significantly correlated with epigenetic age acceleration among older subjects, as well and with global functioning in our sample. Telomere length did not show significant differences between groups, nor did it correlate with epigenetic aging or mtDNA copy number. These results suggest that BD may involve an accelerated epigenetic aging, which might represent a novel target for treating BD and subjects at risk. In particular, our results suggest a complex interplay between biological clocks to determine the accelerated aging and its consequences in BD.

ADHD is associated with migraine: a systematic review and meta-analysis

An association between primary headaches and attention-deficit/hyperactivity disorder (ADHD) has long been suggested. Moreover, headache is regarded as a common side effect of stimulants, the most effective treatment for ADHD. So far, no systematic review has evaluated the potential association between ADHD and headache. We performed a systematic review of the literature and a meta-analysis of all reported studies on ADHD and primary headaches. Our analysis showed a positive association between ADHD and migraine (OR 1.322, 95% CI 1.018–1717, p value 0.036), but not with tension-type headache. There is a significant association between migraine and ADHD. The mechanisms underlying this association remain to be elucidated, warranting further studies.

Integrated transcriptome and methylome analysis in youth at high risk for bipolar disorder: A preliminary analysis

First-degree relatives of patients with bipolar disorder (BD), particularly their offspring, have a higher risk of developing BD and other mental illnesses than the general population. However, the biological mechanisms underlying this increased risk are still unknown, particularly because most of the studies so far have been conducted in chronically ill adults and not in unaffected youth at high risk. In this preliminary study we analyzed genome-wide expression and methylation levels in peripheral blood mononuclear cells from children and adolescents from three matched groups: BD patients, unaffected offspring of bipolar parents (high risk) and controls (low risk). By integrating gene expression and DNA methylation and comparing the lists of differentially expressed genes and differentially methylated probes between groups, we were able to identify 43 risk genes that discriminate patients and high-risk youth from controls. Pathway analysis showed an enrichment of the glucocorticoid receptor (GR) pathway with the genes MED1, HSPA1L, GTF2A1 and TAF15, which might underlie the previously reported role of stress response in the risk for BD in vulnerable populations. Cell-based assays indicate a GR hyporesponsiveness in cells from adult BD patients compared to controls and suggest that these GR-related genes can be modulated by DNA methylation, which poses the theoretical possibility of manipulating their expression as a means to counteract the familial risk presented by those subjects. Although preliminary, our results suggest the utility of peripheral measures in the identification of biomarkers of risk in high-risk populations and further emphasize the potential role of stress and DNA methylation in the risk for BD in youth.

Hippocampal subfield volumes in children and adolescents with mood disorders

The hippocampus has been implicated in various mood disorders, with global volume deficits consistently found in patient populations. The hippocampus, however, consists of anatomically distinct subfields, and examination of specific subfield differences may elucidate the possible molecular mechanisms behind psychiatric pathologies. Indeed, adult studies have reported smaller hippocampal subfield volumes in regions within the cornu ammonis (CA1 and CA4), dentate gyrus (DG), and hippocampal tails in both patients with Major Depressive Disorder (MDD) and Bipolar Disorder (BD) compared to healthy controls. Subfield differences in pediatric patients with mood disorders, on the other hand, have not been extensively investigated. In the current study, magnetic resonance imaging scans were acquired for 141 children and adolescents between the ages of eight and eighteen (57 with BD, 30 with MDD, and 54 healthy controls). An automated segmentation method was then used to assess differences in hippocampal subfield volumes. Children and adolescents with BD were found to have significantly smaller volumes in the right CA1, CA4, and right subiculum, as well as the bilateral granule cell layer (GCL), molecular layer (ML), and hippocampal tails. The volume of the right subiculum in BD patients was also found to be negatively correlated with illness duration. Overall, the findings from this cross-sectional study provide evidence for specific hippocampal subfield volume differences in children and adolescents with BD compared to healthy controls and suggest progressive reductions with increased illness duration.

The Columbia-Suicide Severity Rating Scale: Associations between interrupted, aborted, and actual suicide attempts among adolescent inpatients☆

The Columbia-Suicide Severity Rating Scale divides suicide attempt behaviors into actual, interrupted, and aborted attempts, but limited data have been reported regarding associations between interrupted, aborted, and actual attempts. This study provided initial data on the ability of interrupted and aborted attempts to estimate the frequency of actual suicide attempts. Participants were adolescent psychiatric inpatients (59.9% female), 12-17 years (mean = 14.73, SD = 1.62). Results suggest that interrupted and aborted suicide attempts are associated with the frequency of actual suicide attempts, controlling for suicidal ideation and depressive symptoms. Future research should evaluate whether interrupted and aborted attempts prospectively predicting actual suicide attempts.

Interpersonal Trust and Suicide Ideation Among Adolescent Psychiatric Inpatients: An Indirect Effect via Perceived Burdensomeness

The identification of theoretically and empirically supported correlates of suicide ideation is important to improve treatment approaches to suicide. This study sought to examine the association between interpersonal trust (theoretically conceptualized as a distal risk marker) and suicide ideation in adolescence. Specifically, it was hypothesized that interpersonal trust would be negatively associated with suicide ideation via perceived burdensomeness and thwarted belongingness (conceptualized as more proximal risk markers). Data were drawn from a cross-sectional sample of 387 adolescent inpatients between the ages of 12 and 17xa0years (Mxa0=xa014.72, SDxa0=xa01.49). The sample was 63.6% female, 37.5% Hispanic, 26.9% African American/Black, and 25.8% Caucasian.xa0Adolescents completed a series of self-report measures to assess thwarted belongingness, perceived burdensomeness, interpersonal trust, depressive symptoms, and suicide ideation. A structural equationxa0model was fit to the data, and results demonstrated a significant indirect path from interpersonal trust to suicide ideation via perceived burdensomeness, but not thwarted belongingness. Results suggest that interpersonal trust may be a distal risk marker for suicide ideation and that interventions toxa0increase interpersonal trust may help prevent the development of thwarted belongingness, perceived burdensomeness, and suicide ideation.

Neurocognitive findings in youth at high risk for bipolar disorder: Potential endophenotypes?

Abstract The identification of cognitive markers for bipolar disorder (BD) may lead to the development of personalized preventative and therapeutic approaches for individuals at high risk to develop BD. This chapter summarizes recent structural and functional imaging findings in individuals at high genetic risk for BD. We also include cognitive studies using computerized and pen-and-paper tests investigating nonemotional (“cold”) and emotion-laden (“hot”) facets of cognition. Although few studies have focused on young high-risk individuals, preliminary evidence suggests that these subjects show alterations in regions underlying emotion regulation and cognitive control. Notwithstanding inconsistencies across cognitive studies, findings suggest the presence of verbal memory deficits, slow processing speed, and abnormalities in affective processing. Large-scale, methodologically sound cross-sectional and longitudinal studies are needed to identify reliable cognitive markers of vulnerability in youth at risk for BD.