Aleksandra Lalovic

Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression.

The prefrontal cortex is believed to play a major role in depression and suicidal behavior through regulation of cognition, memory, recognition of emotion, and anxiety-like states, with numerous post-mortem studies documenting a prefrontal serotonergic dysregulation considered to be characteristic of depressive psychopathology. This study was carried out to detect changes in gene expression associated with both suicide and major depression using oligonucleotide microarrays (Affymetrix HG-U133 chip set) summarizing expression patterns in primarily ventral regions of the prefrontal cortex (BA44, 45, 46 and 47). A total of 37 male subjects were included in this study, of which 24 were suicides (depressed suicides=16, nondepressed suicides=8) and 13 were matched controls. All subjects were clinically characterized by means of psychological autopsies using structured interviews. Unique patterns of differential expression were validated in each of the cortical regions evaluated, with group-specific changes highlighting the involvement of several key neurobiological pathways that have been implicated in both suicide and depression. An overrepresentation of factors involved in cell cycle control and cell division (BA44), transcription (BA44 and 47) and myelination (BA46) was seen in gene ontology analysis of differentially expressed genes, which also highlights changes in the expression of genes involved in ATP biosynthesis and utilization across all areas. Gene misexpression in BA46 was most pronounced between the two suicide groups, with many significant genes involved in GABAergic neurotransmission. The pronounced misexpression of genes central to GABAergic signaling and astrocyte/oligodendrocyte function provides further support for a central glial pathology in depression and suicidal behavior.

Cholesterol content in brains of suicide completers

An association between low levels of serum cholesterol and violent or suicidal behaviour has frequently been reported, but it remains unclear how cholesterol in the peripheral system might be related to the brain functions involved in mediating suicidal behaviour. To our knowledge, there have been no previous studies aimed at answering the important question of whether there are differences in cholesterol within the brains of suicide completers. In the present study, cholesterol content was measured in cortical and subcortical tissue of brains from 41 male suicide completers and 21 male controls that died of sudden causes with no direct influence on brain tissue. No significant differences in cholesterol content were found between suicides and controls in the frontal cortex, amygdala or hippocampus. However, when the suicide completers were stratified into violent (n=31) or non-violent (n=10) groups based on the method of death, violent suicides were found to have lower grey-matter cholesterol content overall compared to non-violent suicides [F(1,111)=4.75, p=0.03], specifically in the frontal cortex (t=-4.16, d.f.=37, p<0.0005). Further exploration of the frontal cortex revealed that violent suicides had lower cholesterol content compared to non-violent suicides in the orbitofrontal cortex (t=-2.01, d.f.=36, p=0.05) and the ventral prefrontal cortex (t=-2.49, d.f.=37, p=0.02). This study represents the first direct examination of cholesterol content in brain tissue from suicide completers, and the present findings provide added support for the relationship between low cholesterol and violent or suicidal behaviour.

Suicide and no axis I psychopathology

BackgroundIt is unclear why approximately 10% of suicide completers seem to be psychiatrically normal. To better understand this issue, we studied suicide completers without an axis I diagnosis and compared them, on measures of psychopathology other than axis I, to normal controls and suicide cases with axis I psychopathology.Methods168 suicide cases were examined by way of a psychological autopsy with the best possible informant. Sixteen cases did not meet criteria for an axis I diagnosis; each of these cases was then age and gender matched to 52 suicide completers with an axis I disorder and 110 normal controls.ResultsFourteen of sixteen suicide cases without an axis I diagnosis had detectable abnormalities that were more similar to the axis I diagnosed suicide group than to a living group. Both suicide groups were similar in the total number of past suicide attempts, the total number of individuals with an axis II disorder, and similar scores on measures of impulsive-aggressive behaviors.ConclusionsThese findings suggest that most of the individuals who committed suicide and appeared psychiatrically normal after a psychological autopsy may probably have an underlying psychiatric process that the psychological autopsy method, as commonly carried out, failed to detect.

Alpha 2A adrenergic receptor gene and suicide

Suicide is a complex trait resulting from the interaction of several predisposing factors, among which genes seem to play an important role. Alterations in the noradrenergic system have been observed in postmortem brain studies of suicide victims when compared to controls. The purpose of this study was to test the hypothesis that genetic variants of the alpha(2A) adrenergic receptor gene are implicated in suicide and/or have a modulatory effect on personality traits that are believed to mediate suicidal behavior. We studied a sample of suicides (N=110) and control subjects (N=130) for genetic variation at four loci, including three in the promoter region (g-1800t, c-1291 g and the g-261a) of the alpha(2A) adrenergic receptor gene, and a potentially functional locus, N251K, which leads to an amino acid change (asparagine to lysine). No significant differences were observed at the promoter loci in terms of allelic or genotypic distribution between suicides and controls. However, analysis of the functional polymorphism N251K revealed that the 251 K allele was only present among suicides, though only three suicide cases had this allele, two of which were homozygous. These results are preliminary. If confirmed, they suggest that variation at the alpha(2A) adrenergic receptor gene may play a role in a small proportion of suicide cases.

Altered expression of lipid metabolism and immune response genes in the frontal cortex of suicide completers

BACKGROUND Studies investigating the association between low cholesterol and suicidality have generated a range of ideas about how cholesterol might play a role in influencing suicide risk, extending studies to other aspects of lipid metabolism, as well as immune response, in relation to suicide. METHODS We performed large-scale microarray gene expression analysis using the Affymetrix HG-U133 chipset and focused our investigation on the expression profile of genes related to lipid metabolism and immune response in post-mortem brains from suicide completers and comparison subjects. We used tissue from three regions of the frontal cortex (Brodmann areas (BA) 8/9, 11, and 47) from 22 male suicide completers, 15 of whom were diagnosed with major depressive disorder, and 13 male comparison subjects. RESULTS Fatty acid desaturase (FADS1), leptin receptor (LEPR), phosphoinositide-3-kinase (class 2 alpha; PIK3C2A) and stearoyl-CoA desaturase (SCD) were consistently down-regulated in all three regions of the frontal cortex of depressed suicides compared to comparison subjects, and were among the genes for which significant correlations were observed between our microarray and real-time PCR data. LIMITATIONS Given the absence of a non-suicidal depressed comparison group in this study, it cannot be ascertained whether the gene expression changes identified are associated with depression or suicide. CONCLUSIONS Our findings suggest a role for lipid metabolism and immune response genes in depressed suicide completers and lend further support to the relationship between lipid metabolism and suicidality.

Psychiatric risk factors for motor vehicle fatalities in young men

Background: Motor vehicle accident (MVA) fatalities are an important cause of death in young men. Psychiatric disorders have been shown to be risk factors for MVA, but only a few studies have investigated MVA fatalities. Method: A case–control study was carried out comparing 61 young male MVA fatalities in which the subject was the driver with an equal number of living male subjects matched for age (case by case with no more than 1 years difference between case subjects and control subjects) with the accident group. We assessed both groups, using structured interviews and psychological autopsies. Results: Our results suggest that cluster B personality disorders (borderline and [or] antisocial) (OR 3.54; 95%CI, 1.38 to 16.01) and substance use disorders in the last 6 months (OR 4.33; 95%CI, 1.42 to 9.25) increased the risk of dying in MVAs. In addition, we observed an age effect, where differences in cluster B personality disorders and substance use disorders in the last 6 months were only significantly more prevalent in case subjects aged 26 years or over, compared with control subjects of the same age. Drivers under age 25 years appeared to be comparable with control subjects on all measures of psychopathology. Finally, this interaction between cluster B personality disorders and age over 26 years was the only significant predictor of car fatalities (adjusted OR 16.25; 95%CI, 1.67 to 158.10). Conclusion: Borderline and antisocial personality disorders in which impulsive-aggressive behaviours play a central role and substance use disorders appear to be risk factors for young male deaths in MVAs. Interestingly, this effect seems to be specific to MVA case subjects aged 26 years or over.

Investigation of completed suicide and genes involved in cholesterol metabolism

BACKGROUND Several lines of evidence support the association between low or lowered levels of serum total cholesterol and suicide. Genetic epidemiological studies suggest that genes predispose to suicide. Given that genes control many aspects of cholesterol biosynthesis and metabolism, one approach through which to explore the putative association between low cholesterol and suicide is through genetic studies. METHODS We examined the potential role of five genes encoding proteins involved in cholesterol biosynthesis and transport in a total sample of 305 male Caucasian subjects, consisting of 145 suicide completers and 160 controls. We investigated variation in the HMG CoA reductase (HMGCR), 7-dehydrocholesterol reductase (DHCR7), lipoprotein lipase (LPL), low-density lipoprotein receptor (LDLR), and apolipoprotein E (APOE) genes. RESULTS We were unable to detect significant differences in allele or genotype frequencies between the suicide cases and controls for any of the genes studied. No relationship was found between genotype and impulsivity or aggression as measured using the BIS and BDHI, respectively. LIMITATIONS The limitations of this study are consistent with the typical limitations inherent in most genetic association studies involving complex behavioral traits. CONCLUSION Although these genes are unlikely to play a major role in susceptibility to suicide, further studies in a larger sample are necessary to reveal the smaller genetic effects, if present.

Age and Haplotype Variations within FADS1 Interact and Associate with Alterations in Fatty Acid Composition in Human Male Cortical Brain Tissue

Fatty acids (FA) play an integral role in brain function and alterations have been implicated in a variety of complex neurological disorders. Several recent genomic studies have highlighted genetic variability in the fatty acid desaturase (FADS1/2/3) gene cluster as an important contributor to FA alterations in serum lipids as well as measures of FA desaturase index estimated by ratios of relevant FAs. The contribution to alterations of FAs within the brain by local synthesis is still a matter of debate. Thus, the impact of genetic variants in FADS genes on gene expression and brain FA levels is an important avenue to investigate. Methods Analyses were performed on brain tissue from prefrontal cortex Brodmann area 47 (BA47) of 61 male subjects of French Canadian ancestry ranging in age from young adulthood to middle age (18–58 years old), with the exception of one teenager (15 years old). Haplotype tagging SNPs were selected using the publicly available HapMap genotyping dataset in conjunction with Haploview. DNA sequencing was performed by the Sanger method and gene expression was measured by quantitative real-time PCR. FAs in brain tissue were analysed by gas chromatography. Variants in the FADS1 gene region were sequenced and analyzed for their influence on both FADS gene expression and FAs in brain tissue. Results Our results suggest an association of the minor haplotype with alteration in estimated fatty acid desaturase activity. Analysis of the impact of DNA variants on expression and alternative transcripts of FADS1 and FADS2, however, showed no differences. Furthermore, there was a significant interaction between haplotype and age on certain brain FA levels. Discussion This study suggests that genetic variability in the FADS genes cluster, previously shown to be implicated in alterations in peripheral FA levels, may also affect FA composition in brain tissue, but not likely by local synthesis.

Suicídio e ausência de psicopatologia em eixo I

JUSTIFICATIVA: Todavia no esta claro por que un 10% de las personas que cometen suicidio parecen ser psiquiatricamente normales. Para una mejor comprender este tema, estudiamos suicidas sin diagnostico del eje I y los comparamos con controles normales y con suicidas con psicopatologia del eje I en lo que dice respeto a otras psicopatologias. METODOS: Se han examinado 168 casos de suicidio a traves de autopsia psicologica con el mejor informante disponible. Dieciseis casos no rellenaron los criterios para un diagnostico del eje I; cada uno de estos casos ha sido pareado en edad y genero con 52 casos de suicidio con trastorno del eje I y con 110 controles normales. RESULTADOS: De los 16 casos de suicidio, 14 pacientes sin diagnostico del eje I presentaron anormalidades posibles de detectarse por la autopsia que eran mas semejantes a las encontradas en los pacientes suicidas con diagnostico de eje I que en el grupo vivo. Los dos grupos de suicidad mostraron semejanzas en el numero total de intentos previos de suicidio, en el numero total de individuos con trastornos del eje II y en los resultados obtenidos en la medida de los comportamientos impulsivo-agresivos. CONCLUSIONES: Estos hallazgos sugieren que la mayoria de los individuos que cometio suicidio y aparentaba ser psiquiatricamente normal en la autopsia psicologica, posiblemente tenia algun proceso psiquiatrico subyacente que el metodo de la autopsia, del modo como se hace comunmente, fallo en detectar.

Suicide and no axis I pathology

JUSTIFICATIVA: Todavia no esta claro por que un 10% de las personas que cometen suicidio parecen ser psiquiatricamente normales. Para una mejor comprender este tema, estudiamos suicidas sin diagnostico del eje I y los comparamos con controles normales y con suicidas con psicopatologia del eje I en lo que dice respeto a otras psicopatologias. METODOS: Se han examinado 168 casos de suicidio a traves de autopsia psicologica con el mejor informante disponible. Dieciseis casos no rellenaron los criterios para un diagnostico del eje I; cada uno de estos casos ha sido pareado en edad y genero con 52 casos de suicidio con trastorno del eje I y con 110 controles normales. RESULTADOS: De los 16 casos de suicidio, 14 pacientes sin diagnostico del eje I presentaron anormalidades posibles de detectarse por la autopsia que eran mas semejantes a las encontradas en los pacientes suicidas con diagnostico de eje I que en el grupo vivo. Los dos grupos de suicidad mostraron semejanzas en el numero total de intentos previos de suicidio, en el numero total de individuos con trastornos del eje II y en los resultados obtenidos en la medida de los comportamientos impulsivo-agresivos. CONCLUSIONES: Estos hallazgos sugieren que la mayoria de los individuos que cometio suicidio y aparentaba ser psiquiatricamente normal en la autopsia psicologica, posiblemente tenia algun proceso psiquiatrico subyacente que el metodo de la autopsia, del modo como se hace comunmente, fallo en detectar.