Choi, Doo‐Sup

Suicide is a major public health concern; nevertheless, its neurobiology remains unknown. An area of interest in suicide research is the dorsolateral prefrontal cortex (DLPFC). We aimed to identify altered proteins and potential biological pathways in the DLPFC of individuals who died by suicide employing mass spectrometry-based untargeted proteomics. Postmortem DLPFC from age-matched male suicide mood disorder cases (n = 5) and non-suicide mood disorder cases (n = 5) were compared. The proteins that differed between groups at false discovery rate (FDR) adjusted p-values (Benjamini–Hochberg–Yekutieli) <0.3 and Log2 fold change (FC) >|0.4| were considered statistically significant and were subjected to pathway analysis by Qiagen Ingenuity software. Thirty-three of the 5162 detected proteins showed significantly altered expression levels in the suicide cases and two of them after adjustment for body mass index. The top differentially expressed protein was potassium voltage-gated channel subfamily Q member 3 (KCNQ3) (Log2FC = −0.481, p = 2.10 × 10−09, FDR = 5.93 × 10−06), which also showed a trend to downregulation in Western blot (p = 0.045, Bonferroni adjusted p = 0.090). The most notably enriched pathway was the GABA receptor signaling pathway (p < 0.001). Here, we report a reduction trend of KCNQ3 levels in the DLPFC of male suicide victims with mood disorders. Further studies with a larger sample size and equal sex representation are needed.

BackgroundQuantifying craving longitudinally during the course of withdrawal, early abstinence, and relapse is essential for optimal management of alcohol use disorder (AUD). In an effort to identify biological correlates of craving, we used proton magnetic resonance spectroscopy (1H‐MRS) to investigate the correlation between craving and glutamate levels in the left dorsolateral prefrontal cortex (LDLPFC) of patients with AUD.MethodsParticipants underwent 1H‐MRS of the LDLPFC with 2‐dimensional J‐resolved (2DJ) averaged PRESS. MRS data were processed with LCModel and cerebrospinal fluid (CSF)‐corrected to generate metabolite concentrations. The Penn Alcohol Craving Scale (PACS) and the 30‐day time line follow‐back (TLFB 30) were used to quantify craving for alcohol and drinking patterns, respectively.ResultsThere was a statistically significant positive correlation between CSF‐corrected glutamate ([Glu]) levels and PACS scores (n = 14; p = 0.005). When PACS scores were dichotomized (< or ≥median = 16), [Glu] levels were significantly higher in the high‐ versus low‐craving group (p = 0.007). In addition, there was a significant negative correlation between CSF‐corrected N‐acetyl aspartic acid ([NAA]) levels and mean number of drinks per drinking day in the past month (n = 13; TLFB 30; p = 0.012). When mean TLFB 30 was dichotomized (< or ≥median = 7.86), [NAA] levels were significantly lower in subjects that consumed more alcoholic beverages. There was no significant correlation between [Glu] and [NAA] levels with other measures of drinking behavior and or depression symptom severity.ConclusionsWhile limited by small sample size, these data suggest that glutamate levels in LDLPFC are associated with alcohol craving intensity in patients with AUD. Further study with larger sample size is needed to replicate this finding and evaluate the merits of glutamate spectroscopy as a biological correlate of alcohol craving intensity and a guide to treatment interventions.

ObjectivesThe aim of the present study was to examine N‐acetylaspartate (NAA), a general marker of neuronal viability, and total NAA (tNAA), the combined signal of NAA and N‐acetylaspartylglutamate, in bipolar depression before and after lamotrigine treatment. Given that NAA is synthesized through direct acetylation of aspartate by acetyl‐coenzyme A‐l‐aspartate‐N‐acetyltransferase, we hypothesized that treatment with lamotrigine would be associated with an increase in NAA level.MethodsPatients with bipolar depression underwent two‐dimensional proton magnetic resonance spectroscopy of the anterior cingulate at baseline (n = 15) and after 12 weeks of lamotrigine treatment (n = 10). A group of age‐matched healthy controls (n = 9) underwent scanning at baseline for comparison.ResultsAt baseline, patients with bipolar depression had significantly lower NAA [mean standard deviation (SD) = 1.13 (0.21); p = 0.02] than controls [mean (SD) = 1.37 (0.27)]. Significant increases in NAA [mean (SD) = 1.39 (0.21); p = 0.01] and tNAA [mean (SD) = 1.61 (0.25); p = 0.02] levels were found after 12 weeks of lamotrigine treatment.ConclusionsThese data suggest an NAA deficit in bipolar depression that is normalized after lamotrigine treatment. Future research is warranted to evaluate whether baseline NAA level is a potential biomarker for identifying lamotrigine response patterns and whether this functional brain change has an associated clinical response.

Abstract It is believed that multiple genetic variants with small individual effects contribute to the risk of alcohol dependence. Such polygenic effects are difficult to detect in genome-wide association studies that test for association of the phenotype with each single nucleotide polymorphism (SNP) individually. To overcome this challenge, gene-set analysis (GSA) methods that jointly test for the effects of pre-defined groups of genes have been proposed. Rather than testing for association between the phenotype and individual SNPs, these analyses evaluate the global evidence of association with a set of related genes enabling the identification of cellular or molecular pathways or biological processes that play a role in development of the disease. It is hoped that by aggregating the evidence of association for all available SNPs in a group of related genes, these approaches will have enhanced power to detect genetic associations with complex traits. We performed GSA using data from a genome-wide study of 1165 alcohol-dependent cases and 1379 controls from the Study of Addiction: Genetics and Environment (SAGE), for all 200 pathways listed in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results demonstrated a potential role of the ‘synthesis and degradation of ketone bodies’ pathway. Our results also support the potential involvement of the ‘neuroactive ligand–receptor interaction’ pathway, which has previously been implicated in addictive disorders. These findings demonstrate the utility of GSA in the study of complex disease, and suggest specific directions for further research into the genetic architecture of alcohol dependence.