Large-scale network dynamics in neural response to emotionally negative stimuli linked to serotonin 1A binding in major depressive disorder.

Serotonergic dysfunction is implicated in major depressive disorder (MDD), but the mechanisms of this relationship remain elusive. Serotonin 1A (5-HT1A) autoreceptors regulate brain-wide serotonin neuron firing and are positioned to assert large-scale effects on negative emotion. Here we investigated the relationship between raphe 5-HT1A binding and brain-wide network dynamics of negative emotion. 22 healthy-volunteers (HV) and 27 medication-free participants with MDD underwent positron emission tomography (PET) using [11C]CUMI-101 (CUMI) to quantify 5-HT1A binding in midbrain raphe nuclei and functional magnetic resonance imaging (fMRI) scanning during emotionally negative picture viewing. Causal connectivity across regions responsive to negative emotion was estimated in the fMRI data using a multivariate dynamical systems model. During negative picture viewing, MDD subjects demonstrated significant hippocampal inhibition of amygdala, basal-ganglia, thalamus, orbital frontal cortex, inferior frontal gyrus and dorsomedial prefrontal cortex (IFG, dmPFC). MDD-related connectivity was not associated with raphe 5-HT1A binding. However, greater hippocampal inhibition of amygdala, thalamus, IFG and dmPFC correlated with hippocampal 5-HT1A binding. Correlation between hippocampal 5-HT1A binding and the hippocampal inhibition network was specific to MDD but not HV. MDD and HV groups also differed with respect to the correlation between raphe and hippocampal 5-HT1A binding which was more pronounced in HV. These findings suggest that increased hippocampal network inhibition in MDD is linked to hippocampal serotonergic dysfunction which may in turn arise from disrupted linkage in raphe to hippocampus serotonergic circuitry.

In vivo comparison of N-11CH3 vs O-11CH3 radiolabeled microtubule targeted PET ligands.

Altered dynamics of microtubules (MT) are implicated in the pathophysiology of a number of brain diseases. Therefore, radiolabeled MT targeted ligands that can penetrate the blood brain barrier (BBB) may offer a direct and sensitive approach for diagnosis, and assessing the clinical potential of MT targeted therapeutics using PET imaging. We recently reported two BBB penetrating radioligands, [11C]MPC-6827 and [11C]HD-800 as specific PET ligands for imaging MTs in brain. The major metabolic pathway of the above molecules is anticipated to be via the initial labeling site, O-methyl, compared to the N-methyl group. Herein, we report the radiosynthesis of N-11CH3-MPC-6827 and N-11CH3-HD-800 and a comparison of their in vivo binding with the corresponding O-11CH3 analogues using microPET imaging and biodistribution methods. Both O-11CH3 and N-11CH3 labeled MT tracers exhibit high specific binding and brain. The N-11CH3 labeled PET ligands demonstrated similar in vivo binding characteristics compared with the corresponding O-11CH3 labeled tracers, [11C]MPC-6827 and [11C]HD-800 respectively.

Cognitive and emotional impairments underpinning suicidal activity in patients with mood disorders: an fMRI study.

OBJECTIVE: Mood disorders are strongly associated with suicide, the prevention of which is predicated on timely detection of suicidal activity (ideation, behaviour). Building on our previous work, we sought to determine the nature of neural responses to an emotional-cognitive task in patients with varying degrees of suicidal activity. METHOD: Seventy-nine patients with mood disorders were assessed clinically and scanned using fMRI. Neural responses to an Emotional Face-Word Stroop task were compared with 66 healthy controls. We identified regions of interest from seven key networks and examined responses to incongruent stimuli (Happy face-'Sad' word; Sad face-'Happy' word). RESULTS: In comparison with healthy controls, patients had differential activity during both incongruent conditions. When examining for associations with suicidal activity within the patient group, those with higher scores had decreased default mode network activity for Happy face-'Sad' word manipulation, and increased basal ganglia network activity for Sad face-'Happy' word manipulation, after controlling for patient characteristics. CONCLUSION: The fMRI findings suggest that suicidal activity in patients with mood disorders may be underpinned by cognitive-emotional deficits. These findings have implications for future suicide research and for achieving a deeper understanding of suicidal activity that may ultimately inform clinical detection and management.

Isoform-level brain expression profiling of the spermidine/spermine N1-Acetyltransferase1 (SAT1) gene in major depression and suicide.

Low brain expression of the spermidine/spermine N-1 acetyltransferase (SAT1) gene, the rate-limiting enzyme involved in catabolism of polyamines that mediate the polyamine stress response (PSR), has been reported in depressed suicides. However, it is unknown whether this effect is associated with depression or with suicide and whether all or only specific isoforms expressed by SAT1, such as the primary 171 amino acid protein-encoding transcript (SSAT), or an alternative splice variant (SSATX) that is involved in SAT1 regulated unproductive splicing and transcription (RUST), are involved. We applied next generation sequencing (RNA-seq) to assess gene-level, isoform-level, and exon-level SAT1 expression differences between healthy controls (HC, N = 29), DSM-IV major depressive disorder suicides (MDD-S, N = 21) and MDD non-suicides (MDD, N = 9) in the dorsal lateral prefrontal cortex (Brodmann Area 9, BA9) of medication-free individuals postmortem. Using small RNA-seq, we also examined miRNA species putatively involved in SAT1 post-transcriptional regulation. A DSM-IV diagnosis was made by structured interview. Toxicology and history ruled out recent psychotropic medication. At the gene-level, we found low SAT1 expression in both MDD-S (vs. HC, p = 0.002) and MDD (vs. HC, p = 0.002). At the isoform-level, reductions in MDD-S (vs. HC) were most pronounced in four transcripts including SSAT and SSATX, while reductions in MDD (vs. HC) were pronounced in three transcripts, one of which was reduced in MDD relative to MDD-S (all p < 0.1 FDR corrected). We did not observe evidence for differential exon-usage (i.e. splicing) nor differences in miRNA expression. Results replicate the finding of low SAT1 brain expression in depressed suicides in an independent sample and implicate low SAT1 brain expression in MDD independent of suicide. Low expressions of both SSAT and SATX isoforms suggest that shared transcriptional mechanisms involved in RUST may account for low SAT1 brain expression in depressed suicides. Future studies are required to understand the functions and regulation of SAT1 isoforms, and how they relate to the pathogenesis of MDD and suicide.

Synthesis and in vitro evaluation of [18F]BMS-754807: a potential PET ligand for IGF-1R.

Radiosynthesis and in vitro evaluation of [(18)F](S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide ([(18)F]BMS-754807 or [(18)F]1) a specific IGF-1R inhibitor was performed. [(18)F]1 demonstrated specific binding in vitro to human cancer tissues. Synthesis of reference standard 1 and corresponding bromo derivative (1a), the precursor for radiolabeling were achieved from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (4) in three steps with 50% overall yield. The radioproduct was obtained in 8% yield by reacting 1a with [(18)F]TBAF in DMSO at 170°C at high radiochemical purity and specific activity (1-2Ci/µmol, N=10). The proof of concept of IGF-IR imaging with [(18)F]1 was demonstrated by in vitro autoradiography studies using pathologically identified surgically removed grade IV glioblastoma, breast cancer and pancreatic tumor tissues. These studies indicate that [(18)F]1 can be a potential PET tracer for monitoring IGF-1R.

Ex vivo evaluation of the serotonin 1A receptor partial agonist [³H]CUMI-101 in awake rats.

[³H]CUMI-101 is a 5-HT(1A) partial agonist, which has been evaluated for use as a positron emission tracer in baboon and humans. We sought to evaluate the properties of [³H]CUMI-101 ex vivo in awake rats and determine if [³H]CUMI-101 can measure changes in synaptic levels of serotonin after different challenge paradigms. [³H]CUMI-101 shows good uptake and good specific binding ratio (SBR) in frontal cortex 5.18 and in hippocampus 3.18. Binding was inhibited in a one-binding-site fashion by WAY100635 and unlabeled CUMI-101. The ex vivo B(max) of [³H]CUMI-101 in frontal cortex (98.7 fmol/mg) and hippocampus (131 fmol/kg) agree with the ex vivo B(max) of [³H]MPPF in frontal cortex (147.1 fmol/mg) and hippocampus (72.1 fmol/mg) and with in vitro values reported with 8-OH-DPAT. Challenges with citalopram, a selective serotonin reuptake inhibitor, fenfluramine, a serotonin releaser, and 4-chloro-DL-phenylalanine, a serotonin synthesis inhibitor, did not show any effect on the standardized uptake values (SUVs) in any region. Citalopram did alter SBR, but this was due to changes in cerebellar SUVs. Our results indicate that [³H]CUMI-101 is a good radioligand for imaging 5-HT(1A) high-density regions in rats; however, the results from pharmacological challenges remain inconclusive.

DNA methylation as a risk factor in the effects of early life stress.

Epigenetic marks (e.g., DNA 5-methylcytosine [5mC] content or CpG methylation) within specific gene regulatory regions have been demonstrated to play diverse roles in stress adaptation and resulting health trajectories following early adversity. Yet the developmental programming of the vast majority of the epigenome has not yet been characterized, and its role in the impact of early stress largely unknown. In the present study, we investigated the relationships among early life stress, whole-epigenome and candidate stress pathway gene (serotonin transporter, 5-HTT) methylation patterns, and adult behavioral stress adaptation in a non-human primate model. Early in life, experimental variable foraging demand (VFD) stress or control conditions were administered to two groups each of 10 female bonnet macaques (Macaca radiata) and their mothers. As adults (3-13 years of age), these females were assessed for behavioral adaptation to stress across four conditions of increasing intensity. Blood DNA 5-HTT 5mC status was determined using sodium bisulfite pyrosequencing and total 5mC content was determined using ELISA. Neither stress reactivity nor DNA methylation differed based on early life stress. However, we found that both greater 5-HTT and whole-genome 5mC was associated with enhanced behavioral stress reactivity following early life stress, but not control conditions. Therefore, regardless of developmental origin, greater DNA methylation conferred a genomic background of "risk" in the context of early stress. We suggest that this may arise from constrained plasticity in gene expression needed for stress adaptation early in development. This risk may have wider implications for psychological and physical stress adaptation and health.

Synthesis and in vivo evaluation of [O-methyl-11C] N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide as an imaging probe for 5-HT6 receptors.

The serotonin receptor 6 (5-HT(6)) is implicated in the pathophysiology of cognitive diseases, schizophrenia, anxiety and obesity and in vivo studies of this receptor would be of value for studying the pathophysiology of these disorders. Therefore, N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB399885), a selective and high affinity (pK(i)=9.11) 5-HT(6) antagonist, has been radiolabeled with carbon-11 by O-methylation of the corresponding desmethyl analogue with [(11)C]MeOTf in order to determine the suitability of [(11)C]SB399885 to quantify 5-HT(6)R in living brain using PET. Desmethyl-SB399885 was prepared, starting from 1-(2-methoxyphenyl) piperazine hydrochloride, in excellent yield. The yield obtained for radiolabeling of [(11)C]SB399885 was 30±5% (EOS) and the total synthesis time was 30min at EOB. PET studies with [(11)C]SB399885 in baboon showed fast uptake followed by rapid clearance in the brain. Highest uptake of radioactivity of [(11)C]SB399885 in baboon brain were found in temporal cortex, parahippocampal gyrus, pareital cortex, amygdala, and hippocampus. Poor brain entry and inconsistent brain uptake of [(11)C]SB399885 compared to known 5-HT(6)R distribution limits its usefulness for the in vivo quantification of 5-HT(6)R with PET.

Ventromedial prefrontal cortex/anterior cingulate cortex Glx, glutamate, and GABA levels in medication-free major depressive disorder.

Glutamate (Glu) and gamma-aminobutyric acid (GABA) are implicated in the pathophysiology of major depressive disorder (MDD). GABA levels or GABAergic interneuron numbers are generally low in MDD, potentially disinhibiting Glu release. It is unclear whether Glu release or turnover is increased in depression. Conversely, a meta-analysis of prefrontal proton magnetic resonance spectroscopy (1H MRS) studies in MDD finds low Glx (combination of glutamate and glutamine) in medicated MDD. We hypothesize that elevated Glx or Glu may be a marker of more severe, untreated MDD. We examined ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC) Glx and glutamate levels using 1H MRS in 34 medication-free, symptomatic, chronically ill MDD patients and 32 healthy volunteers, and GABA levels in a subsample. Elevated Glx and Glu were observed in MDD compared with healthy volunteers, with the highest levels seen in males with MDD. vmPFC/ACC GABA was low in MDD. Higher Glx levels correlated with more severe depression and lower GABA. MDD severity and diagnosis were both linked to higher Glx in vmPFC/ACC. Low GABA in a subset of these patients is consistent with our hypothesized model of low GABA leading to glutamate disinhibition in MDD. This finding and model are consistent with our previously reported findings that the NMDAR-antagonist antidepressant effect is proportional to the reduction of vmPFC/ACC Glx or Glu levels.

Depression-related anterior cingulate prefrontal resting state connectivity normalizes following cognitive behavioral therapy.

BACKGROUND: Aberrant activity of the subcallosal cingulate (SCC) is a common theme across pharmacologic treatment efficacy prediction studies. The functioning of the SCC in psychotherapeutic interventions is relatively understudied, as are functional differences among SCC subdivisions. We conducted functional connectivity analyses (rsFC) on resting-state functional magnetic resonance imaging (fMRI) data, collected before and after a course of cognitive behavioral therapy (CBT) in patients with major depressive disorder (MDD), using seeds from three SCC subdivisions. METHODS: Resting-state data were collected from unmedicated patients with current MDD (Hamilton Depression Rating Scale-17 > 16) before and after 14-sessions of CBT monotherapy. Treatment outcome was assessed using the Beck Depression Inventory (BDI). Rostral anterior cingulate (rACC), anterior subcallosal cingulate (aSCC), and Brodmann's area 25 (BA25) masks were used as seeds in connectivity analyses that assessed baseline rsFC and symptom severity, changes in connectivity related to symptom improvement after CBT, and prediction of treatment outcomes using whole-brain baseline connectivity. RESULTS: Pretreatment BDI negatively correlated with pretreatment rACC ~ dorsolateral prefrontal cortex and aSCC ~ lateral prefrontal cortex rsFC. In a region-of-interest longitudinal analysis, rsFC between these regions increased post-treatment (p < 0.05FDR). In whole-brain analyses, BA25 ~ paracentral lobule and rACC ~ paracentral lobule connectivities decreased post-treatment. Whole-brain baseline rsFC with SCC did not predict clinical improvement. CONCLUSIONS: rsFC features of rACC and aSCC, but not BA25, correlated inversely with baseline depression severity, and increased following CBT. Subdivisions of SCC involved in top-down emotion regulation may be more involved in cognitive interventions, while BA25 may be more informative for interventions targeting bottom-up processing. Results emphasize the importance of subdividing the SCC in connectivity analyses.

Lower CSF MHPG predicts short-term risk for suicide attempt.

Post-mortem studies document alterations in the central noradrenergic system in suicide. However, studies of non-fatal suicide attempts have, thus far, found no consistent relationship to the noradrenaline metabolite 3-methoxy-4-hydroxphenylglycol (MHPG) in cerebrospinal fluid (CSF). We therefore conducted a prospective study of CSF MHPG and suicidal acts in major depression and bipolar depression. CSF MHPG was assayed in 184 drug-free patients with DSM-IV major depressive disorder or bipolar disorder, presenting for treatment of a current depressive episode, who were then followed-up for up to 12 months. Survival analysis was conducted using Cox proportional hazards modelling to test association of CSF MHPG and future suicidal behaviour, and potential clinical mediators. Twenty-seven individuals made a suicide attempt (two fatal) in the follow-up period. Lower CSF MHPG predicted future suicide attempt or suicide (22% increase in hazard for each 10 pmol/ml lower MHPG, p=0.045). Lower CSF MHPG also correlated with higher medical lethality of future suicidal act (mean MHPG: 49+/-18 vs. 32+/-12 pmol/ml for low- vs. high-lethality, t=2.8, d.f.=25, p=0.009). Smoking and self-rated depression severity were also associated with lower CSF MHPG and with future suicide attempt, but were not statistically significant mediators in multivariate models. In conclusion, lower CSF MHPG is associated with short-term risk for future suicidal behaviour in the 12 months following a major depressive episode. Psychopathology that mediates the relationship between lower CSF MHPG and future suicidal behaviour needs to be identified.

Substance use disorders and suicide attempts in bipolar subtypes.

Bipolar disorder (BD) is associated with high rates of suicide attempt and completion. Substance use disorders (SUD) have been identified as potent risk factors for suicidal behavior in BD. However, little is known concerning differences between BD subtypes with regard to SUD as a risk factor for suicidal behavior. We studied previous suicidal behavior in adults with a major depressive episode in context of BD type I (BD-I; N=96) or BD type II (BD-II; N=42), with and without history of SUD. Logistic regressions assessed the association between SUD and suicide attempt history by BD type, and exploratory analyses examined the effects of other clinical characteristics on these relationships. SUD were associated with suicide attempt in BD-I but not BD-II, an effect not attributable to sample size differences. The higher suicide attempt rate associated with alcoholism in BD-I was mostly explained by higher aggression scores, and earlier age of BD onset increased the likelihood that alcohol use disorder would be associated with suicide attempt(s). The higher suicide attempt rate associated with other drug use disorders in BD-I was collectively explained by higher impulsivity, hostility, and aggression scores. The presence of both alcohol and drug use disorders increased odds of a history of suicide attempt in a multiplicative fashion: 97% of BD-I who had both co-morbid drug and alcohol use disorders had made a suicide attempt. A critical next question is how to target SUD and aggressive traits for prevention of suicidal behavior in BD-I.

Altered amygdala subregion-related circuits in treatment-naïve post-traumatic stress disorder comorbid with major depressive disorder.

Individuals with both post-traumatic stress disorder and major depressive disorder (PTSD+MDD) often show greater social and occupational impairment and poorer treatment response than individuals with PTSD alone. Increasing evidence reveals that the amygdala, a brain region implicated in the pathophysiology of both of these conditions, is a complex of structurally and functionally heterogeneous nuclei. Quantifying the functional connectivity of two key amygdala subregions, the basolateral (BLA) and centromedial (CMA), in PTSD+MDD and PTSD-alone could advance our understanding of the neurocircuitry of these conditions. 18 patients with PTSD+MDD, 28 with PTSD-alone, and 50 trauma exposed healthy controls (TEHC), all from a cohort who survived the same large earthquake in China, underwent resting-state functional magnetic resonance imaging. Bilateral BLA and CMA functional connectivity (FC) maps were created using a seed-based approach for each participant. The analysis of covariance of FC was used to determine between-group differences. A significant interaction between amygdala subregion and diagnostic group suggested that differences in connectivity patterns between the two seeds were mediated by diagnosis. Post-hoc analyses revealed that PTSD+MDD patients showed weaker connectivity between right BLA and (a) left anterior cingulate cortex/supplementary motor area, and (b) bilateral putamen/pallidum, compared with PTSD-alone patients. Higher CMA connectivities left ACC/SMA were also observed in PTSD+MDD compared with PTSD-alone. An inverse relationship between the connectivity of right BLA with right putamen/pallidum and MDD symptoms was found in PTSD+MDD. These findings indicate a relationship between the neural pathophysiology of PTSD+MDD compared with PTSD-alone and TEHC and may inform future clinical interventions.

Characterization of lipid rafts in human platelets using nuclear magnetic resonance: A pilot study.

Lipid microdomains ('lipid rafts') are plasma membrane subregions, enriched in cholesterol and glycosphingolipids, which participate dynamically in cell signaling and molecular trafficking operations. One strategy for the study of the physicochemical properties of lipid rafts in model membrane systems has been the use of nuclear magnetic resonance (NMR), but until now this spectroscopic method has not been considered a clinically relevant tool. We performed a proof-of-concept study to test the feasibility of using NMR to study lipid rafts in human tissues. Platelets were selected as a cost-effective and minimally invasive model system in which lipid rafts have previously been studied using other approaches. Platelets were isolated from plasma of medication-free adult research participants (n=13) and lysed with homogenization and sonication. Lipid-enriched fractions were obtained using a discontinuous sucrose gradient. Association of lipid fractions with GM1 ganglioside was tested using HRP-conjugated cholera toxin B subunit dot blot assays. 1H high resolution magic-angle spinning nuclear magnetic resonance (HRMAS NMR) spectra obtained with single-pulse Bloch decay experiments yielded spectral linewidths and intensities as a function of temperature. Rates of lipid lateral diffusion that reported on raft size were measured with a two-dimensional stimulated echo longitudinal encode-decode NMR experiment. We found that lipid fractions at 10-35% sucrose density associated with GM1 ganglioside, a marker for lipid rafts. NMR spectra of the membrane phospholipids featured a prominent 'centerband' peak associated with the hydrocarbon chain methylene resonance at 1.3 ppm; the linewidth (full width at half-maximum intensity) of this 'centerband' peak, together with the ratio of intensities between the centerband and 'spinning sideband' peaks, agreed well with values reported previously for lipid rafts in model membranes. Decreasing temperature produced decreases in the 1.3 ppm peak intensity and a discontinuity at ~18 °C, for which the simplest explanation is a phase transition from Ld to Lo phases indicative of raft formation. Rates of lateral diffusion of the acyl chain lipid signal at 1.3 ppm, a quantitative measure of microdomain size, were consistent with lipid molecules organized in rafts. These results show that HRMAS NMR can characterize lipid microdomains in human platelets, a methodological advance that could be extended to other tissues in which membrane biochemistry may have physiological and pathophysiological relevance.

Psychological autopsy of seventy high school suicides: Combined qualitative/quantitative approach.

OBJECTIVE: Suicide is the leading cause of death among Israeli youths but data on causes are scarce. This study used psychological autopsies of 70 Israeli school students who committed suicide during 2004-2011, attempting to determine the causes. METHODS: Four narratives of the self were identified (qualitative analysis) and compared (quantitative analysis): (1) regressive: functioning and mood deteriorated continuously (45%); (2) tragic: doing well until rapid decline around suicidal crisis (20%); (3) unstable: peaks and crises throughout life (20%); and (4) stable: long lasting state of adverse living circumstances (15%). Functioning, mental disorders, stressful life events and substance abuse were examined. RESULTS: A representative profile of the suicide-completer emerged. Suicidality in the tragic narrative involved shorter crisis, fewer risk factors and less psychopathology than the other narratives, also better general functioning and better school performance. Though decrease in functioning was evident in all groups, in the tragic group it tended to be disregarded. CONCLUSION: This study presents an in-depth analysis of a unique suicide population of high school students. A combined methodology of qualitative and quantitative analyses reveals a distinct subpopulation of suicidal adolescents with little or no overt psychopathology that poses a challenge to suicide prevention strategies.

Further evidence of low baseline cortisol levels in suicide attempters.

BACKGROUND: Many, but not all studies of suicide attempters' cortisol response to stress-either social stress or pharmacological challenge-report an exaggerated response. Recent studies of resting baseline cortisol in past suicide attempters, however, have found lower baseline levels. METHODS: In this study, baseline salivary cortisols were obtained prior to a stress procedure from adults with lifetime diagnoses of a mood disorder (N=69), 31.9% of whom had made a prior suicide attempt. Data were collected during the piloting of this stress procedure, at various times of day and with/without an additional confederate in the room. RESULTS: Adjusting for procedural, demographic and clinical variables that affect salivary cortisol levels-including time of day of sampling, order of procedure with respect to other assessments, past alcohol abuse, current medication use, and bipolar diagnosis-past suicide attempters had lower baseline cortisol levels compared to non-attempters. LIMITATIONS: This is a pilot study with modest sample sizes using statistical, rather than experimental control of numerous variables affecting salivary cortisol levels. CONCLUSIONS: Results confirm previous studies. Low baseline cortisol levels have been associated with childhood adversity and externalizing disorders, suggesting a potential role in reducing inhibitions for risky and dangerous behaviors. Further research is needed to more fully characterize these associations and their role in suicidal behavior risk.

Self-Rated Depression Severity Relative to Clinician-Rated Depression Severity: Trait Stability and Potential Role in Familial Transmission of Suicidal Behavior.

Self-rated depression and hopelessness severity are predictors of suicide attempt in major depression. This study evaluated whether: (1) greater self-rated distress relative to severity of clinician-rated depression is a trait; (2) that trait is familial; and (3) that trait is linked to familial transmission of suicidal behavior. A total of 285 mood disorder probands and 457 offspring were assessed twice, at least 1 year apart. Family and subject intra-class correlations for self-report depression and hopelessness, controlling for clinician-rated depression severity, were computed. Mixed general linear models determined offspring-proband correlations. Within-individual intra-class correlation (ICC) for depression-hopelessness was 37.8% (bootstrap 95% CI: 31.0-46.3%). Parent-offspring ICC was 10.7% (bootstrap 95% CI: 3.5-17.8%). Suicide attempt concordant parent-offspring correlation for subjective depression was positive, but negative for attempter parent and nonattempter offspring (p = .0213 for slope interaction). Pessimism was greater in proband or offspring attempters than proband or offspring nonattempters (p < .05). Self-reported hopelessness is partly trait-dependent, and there is modest familial transmission of self-reported depression linked to suicidal behavior that may partly explain familial transmission of suicidal behavior.

Regional heterogeneity of 5-HT1A receptors in human cerebellum as assessed by positron emission tomography.

Two measures used in brain imaging are binding potential (BP) and the specific to nonspecific equilibrium partition coefficient (V(3)''). V(3)'' determined using the 5-HT(1A) ligand [(11)C]WAY-100635 is sensitive to changes in the free and nonspecific binding of the ligand in the reference region (V(2)). Healthy female volunteers have higher 5-HT(1A) BP but not V(3)'' compared with men, because V(2) is higher in women. While there could be several explanations for this observation, we hypothesized that women have more 5-HT(1A) receptors in the cerebellum. We explore the cerebellum to define a subregion that more accurately represents the free and nonspecific binding, potentially allowing the use of V(3)''. A quantitative autoradiogram in human brain using [(3)H]WAY-100635 identified a cerebellar subregion devoid of 5-HT(1A) receptors. In vivo 5-HT(1A) receptors were evaluated using [(11)C]WAY-100635 in 12 healthy women and 13 healthy men. Each subject had a metabolite-corrected arterial input function. The autoradiogram demonstrates the lowest concentration of 5-HT(1A) receptors in the cerebellar white matter (CW) and highest concentration in the cerebellar vermis (CV). The CW volume of distribution (V(T)) is lower than CV. Cerebellar white matter is adequately modeled by a one-tissue compartmental model, while a two-tissue model is necessary to model CV or the total cerebellum (CT). Women have a higher CW V(T) compared with men, suggesting a difference in V(2). Use of CW improves identifiability and time stability of BP in cortical regions. Cerebellar white matter might be a better reference region for use in future 5-HT(1A) studies using [(11)C]WAY-100635. With CW as a reference region, V(3)'' cannot be used to detect differences in 5-HT(1A) receptors between men and women, suggesting the need for arterial input functions to determine BP.

Positron emission tomography of regional brain metabolic responses to a serotonergic challenge in major depressive disorder with and without borderline personality disorder.

Previous neuroimaging studies of major depression have not controlled for the presence of personality disorders characterized by impulsive aggressive behavior, such as borderline personality disorder (BPD). Using positron emission tomography (PET), we studied regional glucose uptake in response to fenfluramine (FEN) in depressed subjects with BPD (n=11) and depressed patients without Cluster B Axis II disorders (n=8). Subjects were scanned while medication-free after a single blind placebo administration and after FEN on a second day. Brain responses were measured by PET imaging of [18F]fluorodeoxyglucose (FDG) and serial prolactin levels. Scans were compared at a voxel level using statistical parametric mapping. Correlations of changes in relative regional cerebral uptake (rCMRglu) with clinical measures were assessed. Depressed borderline patients had greater relative activity in parietotemporal cortical regions (BA 40, BA 22, and BA 42) before and after FEN activation compared to those without BPD. They also had less relative uptake in the anterior cingulate cortex (BA 32) at baseline compared to depressed patients without BPD and FEN abolished this difference. Impulsivity was positively correlated with rCMRglu in superior and middle frontal cortex (BA 6 and 44). Hostility was positively correlated with rCMRglu in temporal cortical regions (BA 21 and 22). In conclusions, borderline pathology in the context of a Major Depressive Disorder is associated with altered activity in parietotemporal and anterior cingulate cortical regions. Controlling for the presence of BPD in future imaging studies of mood disorders may elucidate similarities and differences in regional serotonergic function in these two often comorbid disorders.

Amyloid plaque imaging agent [C-11]-6-OH-BTA-1: biodistribution and radiation dosimetry in baboon.

BACKGROUND: The amyloid neuritic plaque is considered to be a toxic collection of amyloid-ss protein found in brain tissue in Alzheimer's disease. A neutral analogue of the amyloid-binding thioflavin-T (BTA), has been radiolabeled as [C-11]-6-OH-BTA-1. It crosses the blood brain barrier, and is a promising tracer for imaging plaques in vivo using positron emission tomography. We now report the biodistribution and dosimetry of [C-11]-6-OH-BTA-1 in baboons. METHODS: Four 2-hour whole body studies were acquired in an ECAT ACCEL camera in two baboons after the bolus injection of [C-11]-6-OH-BTA-1. After 3.5 minute transmission scans performed per bed position prior to injection, emission scans were collected in 2-D mode over five bed positions. Regions of interest (ROI) were drawn around the brain, left and right lungs, heart, liver, gall bladder, left and right kidneys, spleen and urinary bladder. Since no fluid was removed from the baboons, total body radioactivity was calculated using the injected dose and a calibration factor determined from a cylinder phantom. The area under the curve (AUC) for each ROI was determined by trapezoidal integration of the first few points with subsequent points fit by a decreasing monoexponential. The AUC was then divided by counts in the total body, and resulting residence times were entered into the MIRDOSE3 program. RESULTS: The animals tolerated the procedure well. The ligand was eliminated via the hepatobiliary and renal systems. In the adult male and female reference the gallbladder received the highest estimated radiation dose and was the critical organ (3.9E-02 mGy/MBq and 4.3E-02 mGy/MBq respectively). CONCLUSION: In the United States, the absorbed dose to the gallbladder would limit [C-11]-6-OH-BTA-1 administered with the approval of a Radioactive Drug Research Committee (RDRC) to a single injection of 1295 MBq (35 mCi) in the adult male, and 1314 MBq (35 mCi) in the adult female.