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Biomedical subjects

J John Mann

Publications and source records attributed to J John Mann.

At least 19 recordsLinked to original sources
PubMed2026

Dysregulated adult hippocampal neurogenesis in major depressive disorder.

Major depressive disorder (MDD) is associated with reduced hippocampal volume, altered connectivity and negative memory bias, suggesting disrupted hippocampal plasticity. Dysregulated adult hippocampal neurogenesis is a potential contributor, but its relevance in humans and role in MDD remain unclear. Here we investigated the molecular basis of hippocampal dysfunction in nonmedicated individuals with MDD by integrating analyses of neurogenic trajectories, cell-type- and subfield-specific gene expression, chromatin accessibility and protein expression. We identify a neurogenic lineage in the adult human hippocampal subgranular zone and provide evidence for a stalled neurogenic process in MDD, associated with transcriptional regulation, stress-related reprogramming and interferon signaling across developmental stages. Excitatory and inhibitory neurons show dysregulation of transcription factor networks affecting cell states. Cellular stress, excitatory-inhibitory imbalance, impaired synaptic plasticity, reduced metabolic capacity and immune activation, underlie impaired neurogenesis and reduced hippocampus circuit plasticity. Findings indicate genetic and epigenetic regulation of gene expression in MDD, and overlapping pathogenetic mechanisms with autoimmune, neurodevelopmental and neurodegenerative diseases. This work provides a new understanding of the pathogenesis of hippocampus-dependent cognitive symptoms in MDD and suggests potential therapeutic targets.

Journal Article↗
PubMed2004

Synthesis of [O-methyl-11C]1-(2-chlorophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide: a potential PET ligand for CB1 receptors.

Synthesis and in vitro evaluation of [O-methyl-(11)C]1-(2-chlorophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide ([(11)C]-1), a potential imaging agent for CB(1) receptors using PET is described. 1-(2-Chlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (5), the precursor for radiolabeling, was synthesized from 4-OTBDPS-propiophenone (2) in five steps with 30% overall yield. The reaction of alcohol 5 with [(11)C]MeOTf at 60 degrees C afforded [(11)C]-1 with an average radiochemical yield of 14.5% (EOS) and >2000 Ci/mmol specific activity. The radiotracer was found to selectively label CB(1) receptors in slide-mounted sections of postmortem human brain containing prefrontal cortex as demonstrated by in vitro autoradiography using phosphor imaging.

Autoradiography↗
PubMed2004

Genetics of monoamine metabolites in baboons: overlapping sets of genes influence levels of 5-hydroxyindolacetic acid, 3-hydroxy-4-methoxyphenylglycol, and homovanillic acid.

BACKGROUND: Monoamine neurotransmitters (serotonin, dopamine, and norepinephrine) are associated with several psychiatric disorders. Limited evidence suggests that monoamine levels are heritable, but no information concerning genetic relationships among monoamines is available. Further genetic analysis can help explain phenotypic correlations among monoamine levels and might eventually help identify genes involved in response to therapy or risk of psychopathology. METHODS: Levels of the monoamine metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-hydroxy-4-methoxyphenylglycol (MHPG) were measured in cerebrospinal fluid from 271 baboons (Papio hamadryas). Variance components methods were used to estimate heritabilities, and multivariate analyses were used to estimate genetic correlations (pleiotropy) and environmental correlations between metabolites. RESULTS: Each metabolite exhibited significant heritability in baboons (5-HIAA: h(2) =.30 +/-.17; MHPG: h(2) =.36 +/-.16; HVA: h(2) =.50 +/-.19). Multivariate analyses revealed genetic correlations between 5-HIAA and HVA and between HVA and MHPG. Environmental correlations were found between 5-HIAA and HVA and between 5-HIAA and MHPG. CONCLUSIONS: Overlapping, nonidentical sets of genes influence individual variation in 5-HIAA, MHPG, and HVA levels among baboons. The phenotypic correlation between 5-HIAA and HVA observed in nonhuman primates and humans is likely due to both shared genetic and environmental factors. Genetic analyses of monoamine levels in primates can provide novel information concerning the genetics of variation among humans.

Analysis of Variance↗
PubMed2004

Chiral synthesis of (2S,3S)-2-(2-morpholin-2-yl-2-phenylmethoxy)phenol.

Resolution of (2RS,3RS)-2-[alpha-(2-methoxymethoxyphenoxy)phenylmethyl]morpholine, 11, with (+) mandelic acid led to the formation of (+)-(2S,3S)-2-[alpha-(2-methoxymethoxyphenoxy)phenyl methyl] morpholine (11a). Compound 11 was synthesized in seven steps from (2RS,3RS)-cinnamyl alcohol-2,3-epoxide (4), with an overall yield of 17%. Cleavage of the methoxymethyl group of the Fmoc derivative 12 with catalytic amounts of p-toluenesulfonic acid in methanol afforded (+)-(2S,3S)-2-(2-morpholin-2-yl-2-phenylmethoxy)phenol 2. The synthetic utility as well as the configuration of compound 2 has been demonstrated by converting (S,S)-2-(2-morpholin-2-yl-2-phenylmethoxy)phenol 2 to (2S,3S)-2-[alpha-(2-ethoxyphenoxy)phenylmethyl]morpholine (1) and (2S,3S)-2-(2-methoxyphenoxy) benzyl)morpholine (16), two potential norepinephrine reuptake inhibitors under clinical evaluation.

Antidepressive Agents↗
PubMed2004

OS-EM and FBP reconstructions at low count rates: effect on 3D PET studies of [11C] WAY-100635.

11C-labeled neuroreceptor ligands frequently require long scan durations to quantify ligand-receptor binding. In this paper, we compare the accuracy of two three-dimensional (3D) positron emission tomography (PET) reconstructions: ordered-subset expectation-maximization (OS-EM) versus filtered backprojection (FBP) under low count rate conditions exhibited by 11C neuroreceptor studies. Data were obtained from a dynamic 11C phantom acquisition as well as six dynamic human [11C] WAY-100635 studies, all acquired in 3D mode using the EXACT HR+ PET scanner. Model-based scatter correction of the phantom datum was found to overcorrect in low count rate situations producing a negative bias in FBP reconstruction and a positive bias in OS-EM reconstruction, the OS-EM bias attributed to the non-negativity constraint of sinogram values. In the phantom OS-EM and FBP, reconstruction bias occurred at activities less than 25 Bq/cm3. In the human cerebellum, OS-EM deviated from FBP at activities less than 50 Bq/cm3. The total volume of distribution (VT), as determined from the metabolite corrected arterial input function and a two-tissue compartment kinetic model, was more sensitive to the positive bias of OS-EM than the negative bias of FBP at low count rates. To avoid reconstruction bias with 3D PET studies using the HR+, the scan duration should be limited so as to yield a final non-decay-corrected activity concentration of no less than 50 Bq/cm3. In neuroreceptor studies, if such a low count rate cannot be avoided, FBP reconstruction is preferable to OS-EM to estimate VT.

Algorithms↗
PubMed2004

Gene expression profiling of depression and suicide in human prefrontal cortex.

Mood disorders are a major cause of disability. Etiology includes genetic and environmental factors, but the responsible genes have yet to be identified. Using DNA microarrays, we have conducted a large-scale gene expression analysis, in two regions of the human prefrontal cortex from post-mortem matched groups of subjects with major depression who had died by suicide, and control subjects who died from other causes and were free from psychiatric disorders. Bioinformatic analysis was used to investigate molecular and cellular pathways potentially involved in depression and suicidal behavior. We tested several hypotheses of disease pathology and of their putative molecular impact, including changes in single genes, the existence of subgroups of patients or disease subtypes, or the possibility of common biological pathways being affected in the disease process. Within the analytical limits of this relatively large genomic study, we found no evidence for molecular differences that correlated with depression and suicide, suggesting a pathology that is below the detection level of current genomic approaches, or that is either localized to other brain areas, or more associated with post-transcriptional effects and/or changes in protein levels or functions, rather than altered transcriptome in the prefrontal cortex.

Adult↗
PubMed2004

Volumetric analysis of the prefrontal cortex, amygdala, and hippocampus in major depression.

Magnetic resonance imaging (MRI) studies in depressed subjects report smaller volumes of amygdala, hippocampus, inferior anterior cingulate, and the orbital prefrontal cortex (OPFC), components of the limbic-cortico-thalamic circuit. Major depression occurs more commonly in women, raising the possibility of an additional psychopathological process affecting women and not men. We sought to determine whether volumetric differences related to mood disorders are dependent on sex. Eight male and 10 female depressed subjects, meeting DSM III R criteria for a major depressive episode, and eight male and 10 female healthy volunteers had MRI scans on a 1.5 T GE Signa Advantage scanner. The regions of interest included amygdala, hippocampus, inferior anterior cingulate, and OPFC. In all analyses, regional volumes were normalized for total cerebral volume. Volumetric changes in the ROIs showed a significant sex by diagnosis interaction, indicating a different pattern of volumetric changes in depressed males compared with females relative to controls. Relative to sex-matched controls, the left inferior anterior cingulate was smaller in depressed males (23%) compared with depressed females (11%). Depressed females but not depressed males had smaller amygdala compared with controls (F-value = 4.946, p = 0.033). No significant volumetric differences were noted in the hippocampus or OPFC. No volumetric correlations were noted with clinical variables, depression subtypes, or a reported history of sexual or physical abuse. Sex may affect volumetric deficits in amygdala and anterior cingulate cortex in mood disorders, but no effects were found in the hippocampus or OPFC. The biology of mood disorders in females may differ in some aspects from males, and may contribute to the higher rate of depression in women.

Adult↗
PubMed2004

An association between a functional polymorphism in the monoamine oxidase a gene promoter, impulsive traits and early abuse experiences.

Monoamine oxidase A (MAOA) activity is altered in mood disorders and lower activity associated with aggressive behavior. The gene has a functional polymorphism with a variable number tandem repeat (VNTR) in the upstream regulatory region (MAOA-uVNTR). In this study, we examined possible associations between the MAOA-uVNTR polymorphism and mood disorders, suicidal behavior, aggression/impulsivity, and effects of reported childhood abuse. In total, 663 unrelated subjects with a psychiatric disorder and 104 healthy volunteers were genotyped for the 30 base pair functional VNTR. A novel repeat variation was identified. No statistically significant associations were found between this functional MAOA-uVNTR polymorphism and mood disorders or suicide attempts. However, the lower expression allele was associated with a history of abuse before 15 years of age in male subjects and with higher impulsivity in males but not females. Our results suggest that the lower expression of the MAOA-uVNTR polymorphism is related to a history of early abuse and may sensitize males, but not females, to the effects of early abuse experiences on impulsive traits in adulthood. The polymorphism may be a marker for impulsivity that in turn may contribute to the risk for abuse. This trait could then be further aggravated by abuse.

Adult↗
PubMed2004

Instability of symptoms in recurrent major depression: a prospective study.

OBJECTIVE: Recurrent episodes of major depressive disorder are reported to have similar or stable characteristics across episodes. However, symptoms appear to be moderately stable only in consecutive depressive episodes or if episode severity is considered. The authors prospectively studied major depressive episodes occurring within 2 years to determine whether symptoms in the second episode could be predicted on the basis of symptoms in the first. METHOD: Inpatients (N=78) with major depressive disorder were rated with the Hamilton Depression Rating Scale during two separate episodes. Patients had a baseline assessment at index hospitalization and follow-up visits at 3, 12, and 24 months after discharge. Information regarding the presence of a major depressive episode, its duration, and its severity was documented. Baseline and follow-up data were analyzed by using Pearson correlations with and without adjustments for severity of depression. RESULTS: Subtype of depression appeared not to be stable. The most robust, although still weak, correlations across episodes were for anxiety and suicidal behavior. Only modest correlations were identified for a few depressive symptoms. CONCLUSIONS: The lack of robust consistency of symptoms or depressive subtype across episodes is striking given the requirement of five of nine predetermined symptoms for depression, increasing the chances of finding an association. These findings suggest that there is a superfamily of mood disorders with pleomorphic manifestations across major depressive episodes within individual patients with unipolar depression.

Adolescent↗
PubMed2004

Suicidal behavior in schizophrenia and schizoaffective disorder: examining the role of depression.

Understanding the relationship between depression and suicidal behavior among individuals with schizophrenia and schizoaffective disorder can aid assessment and treatment. In this study, 86 individuals with schizophrenia and schizoaffective disorder were assessed for past and current suicidal behavior, depression, hopelessness, and reasons for living. Thirty-four percent reported a history of suicide attempts. Suicidal behavior typically occurred 4.5 years after the onset of psychosis and 7.5 years after the onset of the first major depressive episode for those who had a history of major depression. Depression was frequent among both attempters and non-attempters, but only half of the attempters reported a suicide attempt during an episode of major depression. And almost half of those with depression never made a suicide attempt despite a long history of illness. Although depression is a potential stressor for triggering suicidal behavior in a vulnerable subset of individuals with schizophrenia, schizophrenia research must identify other risk factors for suicidal behavior. Clinicians should remember that even without a depressive episode there is still a significant risk for suicidal behavior in schizophrenia.

Adult↗
PubMed2003

Sex genes for genomic analysis in human brain: internal controls for comparison of probe level data extraction.

BACKGROUND: Genomic studies of complex tissues pose unique analytical challenges for assessment of data quality, performance of statistical methods used for data extraction, and detection of differentially expressed genes. Ideally, to assess the accuracy of gene expression analysis methods, one needs a set of genes which are known to be differentially expressed in the samples and which can be used as a "gold standard". We introduce the idea of using sex-chromosome genes as an alternative to spiked-in control genes or simulations for assessment of microarray data and analysis methods. RESULTS: Expression of sex-chromosome genes were used as true internal biological controls to compare alternate probe-level data extraction algorithms (Microarray Suite 5.0 [MAS5.0], Model Based Expression Index [MBEI] and Robust Multi-array Average [RMA]), to assess microarray data quality and to establish some statistical guidelines for analyzing large-scale gene expression. These approaches were implemented on a large new dataset of human brain samples. RMA-generated gene expression values were markedly less variable and more reliable than MAS5.0 and MBEI-derived values. A statistical technique controlling the false discovery rate was applied to adjust for multiple testing, as an alternative to the Bonferroni method, and showed no evidence of false negative results. Fourteen probesets, representing nine Y- and two X-chromosome linked genes, displayed significant sex differences in brain prefrontal cortex gene expression. CONCLUSION: In this study, we have demonstrated the use of sex genes as true biological internal controls for genomic analysis of complex tissues, and suggested analytical guidelines for testing alternate oligonucleotide microarray data extraction protocols and for adjusting multiple statistical analysis of differentially expressed genes. Our results also provided evidence for sex differences in gene expression in the brain prefrontal cortex, supporting the notion of a putative direct role of sex-chromosome genes in differentiation and maintenance of sexual dimorphism of the central nervous system. Importantly, these analytical approaches are applicable to all microarray studies that include male and female human or animal subjects.

Algorithms↗
PubMed2003

Impulsivity, gender, and response to fenfluramine challenge in borderline personality disorder.

Behavioral impulsivity in borderline personality disorder (BPD) is associated with indices of diminished central serotonergic function, independent of suicidal behavior, depression or alcohol use disorder. Many of these studies have been conducted among males in specialized settings. Studies of BPD females, who constitute the majority of BPD patients, are generally conducted in community settings and report inconsistent findings. We studied gender differences in behavioral impulsivity and the prolactin response to D,L-fenfluramine (FEN) in BPD subjects in a community setting. A FEN challenge study was conducted with 64 BPD subjects (20 male, 44 female), and 57 controls (36 male, 21 female). Axis I and II disorders, including BPD, and suicidal histories were assessed by structured interviews. Controls were free of Axis I and II disorders. Impulsivity and aggression were assessed by the Buss-Durkee Hostility Inventory, Barratt Impulsiveness Scale, Minnesota Multiphasic Personality Inventory-Psychopathic Deviate subscale, and the Brown-Goodwin Lifetime History of Aggression. Male, but not female, BPD subjects had significantly diminished prolactin responses compared to controls. Impulsivity and aggression each predicted prolactin responses. A significant effect of BPD diagnosis on prolactin response was eliminated when impulsivity was co-varied. Impulsivity and aggression were inversely related to delta-prolactin and peak-prolactin responses among male but not female subjects. Gender differences in central serotonergic function may contribute to variations in impulsivity in BPD.

Adult↗
PubMed2003

Lower CSF homovanillic acid levels in depressed patients with a history of alcoholism.

Major depression and alcoholism are often comorbid, resulting in more impairment and more suicidal behavior compared with either diagnosis alone. This study compared clinical features and cerebrospinal fluid (CSF) monoamine metabolites in depressed subjects with and without a history of alcoholism and healthy volunteers. We hypothesized that depressed subjects with a history of alcoholism would be more aggressive, impulsive, and suicidal than depressed subjects without a history of alcoholism, and would have lower CSF monoamine metabolite levels. We compared 63 subjects with a current major depressive episode (MDE) and a history of alcoholism, 72 subjects with a current MDE but without a history of alcoholism, and 22 healthy volunteers. Participants with a history of alcoholism were in remission for at least 6 months. All subjects were free from prescribed medications known to affect brain serotonin, dopamine, or norepinephrine systems for a minimum of 14 days. Depressive symptoms, lifetime aggression, impulsivity, Axis II disorders, and suicidal behavior were assessed. CSF was sampled and homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were assayed by high-performance lipid chromatography with electrochemical detection. Depressed subjects with a history of alcoholism did not differ from depressed subjects without a history of alcoholism in current severity of depressive symptoms, or in past suicidal behavior. Depressed subjects with a history of alcoholism had lower CSF HVA levels, and higher lifetime aggression and current suicide ideation scale scores and were more likely to be tobacco smokers compared with depressed subjects without a history of alcoholism. Low HVA was present after adjustment for sex, aggression and depression scores, cigarette smoking, antisocial and borderline personality disorders, psychomotor retardation, and delusions. Controls had CSF HVA levels intermediate between the two depressed groups. We found no group difference in CSF 5-HIAA and MHPG levels. In individuals with current MDE, those with a history of comorbid alcoholism had lower CSF HVA levels compared with those without a history of alcoholism. Low CSF HVA suggests that impaired dopaminergic activity is associated with a history of alcoholism in persons with current MDE.

Adult↗
PubMed2003

Differentiating depressed adolescent 24 h cortisol secretion in light of their adult clinical outcome.

A clinical follow-up study was performed of adolescent major depressives and normal control subjects approximately 10 years after the subjects had undergone serial cortisol measurements over a 24-h period. In light of their young adulthood clinical status, our objective was to ascertain whether there were any premorbid cortisol abnormalities associated with depressive course of illness. In all, 77 young adults who had received a diagnosis of adolescent major depressive disorder, or were determined to be normal volunteers free of psychiatric diagnosis at index period and during follow-up, were studied. When subjects were adolescents, blood samples were collected for cortisol at 20-min intervals during the 24-h period coinciding with the third consecutive night of sleep EEG. The subjects, in young adulthood at the time of follow-up, were reinterviewed regarding longitudinal course of illness, and the original adolescent cortisol data were analyzed in the light of information obtained. Of the subjects who had experienced at least one lifetime major depressive episode during the follow-up period, the subgroup who would go on to make suicide attempts during the follow-up period secreted significantly greater levels of cortisol in the 4, 6, and 12 h prior to sleep onset. Conversely, this same subgroup exhibited reduced cortisol levels 2-4 h following sleep onset. Adolescents who are at risk to make suicide attempts appear to display significant elevations of cortisol prior to sleep onset, a time when the hypothalamic-pituitary-adrenal (HPA) axis is normally most quiescent. Dysregulation of the HPA axis, combined with dysfunction of sleep-onset mechanisms previously reported in this same cohort, might serve as premorbid biological substrates that predict suicide attempts during follow-up.

Adolescent↗
PubMed2003

Positron emission tomography of regional brain metabolic responses to a serotonergic challenge and lethality of suicide attempts in major depression.

BACKGROUND: Lower serotonergic activity correlates with high-lethality suicide attempts in major depression. Postmortem studies of serotonin receptors in suicides localize changes to the ventral prefrontal cortex (PFC). We studied serotonergic response in ventral PFC in depressed patients surviving a high-lethality suicide attempt. METHODS: Depressed patients with a history of a high-lethality suicide attempt (n = 16) were compared with those with low-lethality attempts (n = 9) for level of depression, suicidal intent and ideation, impulsivity, aggression, and neuropsychological test performance. Subjects were scanned while medication free after a single-blind placebo and after fenfluramine hydrochloride administration on a second day. Brain responses were measured by positron emission tomography imaging of fludeoxyglucose F 18 and serial prolactin levels. Scans were compared by means of statistical parametric mapping. Correlations of changes in relative regional cerebral uptake (rCMRglu) with clinical and neuropsychological measures were assessed. RESULTS: Depressed high-lethality suicide attempters had lower rCMRglu in ventral, medial, and lateral PFC compared with low-lethality attempters. This difference was more pronounced after fenfluramine administration. Lower ventromedial PFC activity was associated with lower lifetime impulsivity, higher suicidal intent (planning), and higher-lethality suicide attempts. Higher verbal fluency was positively correlated with rCMRglu in the same regions. CONCLUSIONS: Prefrontal localized hypofunction and impaired serotonergic responsivity are proportional to the lethality of the suicide attempt and may mediate the effects of suicide intent and impulsivity on lethality. Positron emission tomographic neuroreceptor studies are needed to determine whether postmortem serotonin receptor findings are also present in vivo and contribute to the abnormal rCMRglu responses.

Adult↗
PubMed2003

Clinical impact of a 2-week psychotropic medication washout in unipolar depressed inpatients.

BACKGROUND: Short-term discontinuation of psychiatric medications is required in many types of research studies. Yet there are few studies of the clinical impact of psychotropic discontinuation. We studied the impact of a short-term medication washout in unipolar depressed patients consecutively admitted to hospital for neuroimaging and cerebrospinal fluid (CSF) studies. METHOD: Patients (n=51) with unipolar depression who were taking antidepressant or mood stabilizing medication at or within 1 week of admission, and who had not been responding satisfactorily, were assessed for severity of psychopathology within 1 week of hospital admission and 41 of the group were reassessed following an approximately 2-week medication washout. RESULTS: On average, patients remained stable during the washout or improved on clinical measures. No serious adverse clinical changes were observed. LIMITATIONS: Potential sample bias, small sample size. CONCLUSION: The results suggest that similar studies can be conducted without causing undue worsening of symptoms. The benefit of medication washout may be related to the fact that many of the patients had been responding poorly to the medication they were taking. There is a need for further research on the effects of medication washout, for example in outpatients or those who are responding well to treatment, but have intolerable side-effects.

Adult↗