Corticotropin-releasing factor overexpression gives rise to sex differences in Alzheimer's disease-related signaling.

Several neuropsychiatric and neurodegenerative disorders share stress as a risk factor and are more prevalent in women than in men. Corticotropin-releasing factor (CRF) orchestrates the stress response, and excessive CRF is thought to contribute to the pathophysiology of these diseases. We previously found that the CRF1 receptor (CRF1) is sex biased whereby coupling to its GTP-binding protein, Gs, is greater in females, whereas ß-arrestin-2 coupling is greater in males. This study used a phosphoproteomic approach in CRF-overexpressing (CRF-OE) mice to test the proof of principle that when CRF is in excess, sex-biased CRF1 coupling translates into divergent cell signaling that is expressed as different brain phosphoprotein profiles. Cortical phosphopeptides that distinguished female and male CRF-OE mice were overrepresented in unique pathways that were consistent with Gs-dependent signaling in females and ß-arrestin-2 signaling in males. Notably, phosphopeptides that were more abundant in female CRF-OE mice were overrepresented in an Alzheimer's disease (AD) pathway. Phosphoproteomic results were validated by demonstrating that CRF overexpression in females was associated with increased tau phosphorylation and, in a mouse model of AD pathology, phosphorylation of ß-secretase, the enzyme involved in the formation of amyloid ß. These females exhibited increased formation of amyloid ß plaques and cognitive impairments relative to males. Collectively, the findings are consistent with a mechanism whereby the excess CRF that characterizes stress-related diseases initiates distinct cellular processes in male and female brains, as a result of sex-biased CRF1 signaling. Promotion of AD-related signaling pathways through this mechanism may contribute to female vulnerability to AD.

Corticosterone and related receptor expression are associated with increased beta-amyloid plaques in isolated Tg2576 mice.

Previously, we reported that the stress associated with chronic isolation was associated with increased beta-amyloid (Abeta) plaque deposition and memory deficits in the Tg2576 transgenic animal model of Alzheimer's disease (AD) [Dong H, Goico B, Martin M, Csernansky CA, Bertchume A, Csernansky JG (2004) Effects of isolation stress on hippocampal neurogenesis, memory, and amyloid plaque deposition in APP (Tg2576) mutant mice. Neuroscience 127:601-609]. In this study, we investigated the potential mechanisms of stress-accelerated Abeta plaque deposition in this Tg2576 mice by examining the relationship between plasma corticosterone levels, expression of glucocorticoid receptor (GR) and corticotropin-releasing factor receptor-1 (CRFR1) in the brain, brain tissue Abeta levels and Abeta plaque deposition during isolation or group housing from weaning (i.e. 3 weeks of age) until 27 weeks of age. We found that isolation housing significantly increased plasma corticosterone levels as compared with group-housing in both Tg+ mice (which contain and overexpress human amyloid precursor protein (hAPP) gene) and Tg- mice (which do not contain hAPP gene as control). Also, isolated, but not group-housed animals showed increases in the expression of GR in the cortex. Furthermore, the expression of CRFR1 was increased in isolated Tg+ mice, but decreased in isolated Tg- mice in both cortex and hippocampus. Changes in the components of hypothalamic-pituitary-adrenal (HPA) axis were accompanied by increases in brain tissue Abeta levels and Abeta plaque deposition in the hippocampus and overlying cortex in isolated Tg+ mice. These results suggest that isolation stress increases corticosterone levels and GR and CRFR1 expression in conjunction with increases in brain tissue Abeta levels and Abeta plaque deposition in the Tg2576 mouse model of AD.

Predictors of risk for relapse in patients with schizophrenia or schizoaffective disorder during olanzapine drug therapy.

PURPOSE: To evaluate the relationship of dose decrease, symptom worsening, and baseline covariates on subsequent relapse during olanzapine treatment in patients with schizophrenia or schizoaffective disorder. METHODS: In two 28-week, randomized, double-blind clinical trials, a Cox proportional hazards model was used to determine potential correlates of relapse (defined as > or =20% worsening on PANSS total and CGI-Severity 3) among patients (N=271) who responded to 8 weeks of olanzapine treatment (10-20mg/day). Variables examined included: demographics, illness characteristics, baseline symptoms, symptom change, dose, adverse events, and functioning. RESULTS: Patients with a lower last dose relative to the preceding visit interval were 4 times more likely to relapse during that visit interval than other patients (p<.001). A similar finding was observed for a decrease in interval modal dose, although this variable was more predictive of relapse in the visit interval immediately following dose decrease (p=.027). In a subgroup analysis by gender, there was a significantly greater incidence of relapse in men with a dose decrease, whereas a dose decrease in women did not correlate with relapse. Relapse was also correlated with the emergence or worsening of a psychiatric adverse event during the same (p<.001) and preceding (p=.007) visit intervals, and with increased rating scale measures of psychopathology. The occurrence of a non-psychiatric adverse event was not associated with relapse. CONCLUSION: Dose decrease is a significant predictor of relapse in male but not female patients. Psychiatric adverse events also predicted relapse. Patients should be periodically reassessed to determine the need for maintenance treatment with appropriate dose.

Shape mapping of the hippocampus in young children with autism spectrum disorder.

BACKGROUND AND PURPOSE: We hypothesized the occurrence of characteristic hippocampal-shape alterations in young children with autistic spectrum disorder (ASD) who also exhibit deficits on neuropsychologic tests of medial temporal lobe (MTL) function. MATERIALS AND METHODS: Coronal 3D MR images were acquired from 3- to 4-year-old children with ASD (n = 45) and age-matched children with typical development (n = 13). Children with ASD were further subclassified into those with autism disorder (AD, n = 29) or pervasive developmental disorder-not otherwise specified (PDD-NOS) (n = 16). Variations in hippocampal shape were evaluated by using large-deformation high-dimensional brain mapping. RESULTS: Hippocampal shape measures distinguished children with ASD from those with typical development; within the ASD sample, children with AD were distinguished from those with PDD-NOS. Hippocampal-shape alterations in children with ASD were correlated with degree of mental retardation and performance deficits on tests of MTL function. CONCLUSIONS: Children with ASD exhibited an alteration of hippocampal shape consistent with inward deformation of the subiculum. This pattern of hippocampal-shape deformations in the children with ASD was accentuated in the more severely affected subgroup of children with AD and was associated with deficits on neuropsychologic tests of MTL but not prefrontal function. Hippocampal-shape deformation in the children with ASD was observed to be similar to a pattern of hippocampal shape deformation previously reported in adults with MTL epilepsy. Although the children with ASD, and those with AD in particular, PDD-NOS are at high risk for epilepsy as they enter adolescence, the specificity and causal relationship of this pattern of hippocampal-shape deformation to the development of seizures is not yet known.

Predictive value of hippocampal MR imaging-based high-dimensional mapping in mesial temporal epilepsy: preliminary findings.

BACKGROUND AND PURPOSE: We objectively assessed surface structural changes of the hippocampus in mesial temporal sclerosis (MTS) and assessed the ability of large-deformation high-dimensional mapping (HDM-LD) to demonstrate hippocampal surface symmetry and predict group classification of MTS in right and left MTS groups compared with control subjects. METHODS: Using eigenvector field analysis of HDM-LD segmentations of the hippocampus, we compared the symmetry of changes in the right and left MTS groups with a group of 15 matched controls. To assess the ability of HDM-LD to predict group classification, eigenvectors were selected by a logistic regression procedure when comparing the MTS group with control subjects. RESULTS: Multivariate analysis of variance on the coefficients from the first 9 eigenvectors accounted for 75% of the total variance between groups. The first 3 eigenvectors showed the largest differences between the control group and each of the MTS groups, but with eigenvector 2 showing the greatest difference in the MTS groups. Reconstruction of the hippocampal deformation vector fields due solely to eigenvector 2 shows symmetrical patterns in the right and left MTS groups. A "leave-one-out" (jackknife) procedure correctly predicted group classification in 14 of 15 (93.3%) left MTS subjects and all 15 right MTS subjects. CONCLUSION: Analysis of principal dimensions of hippocampal shape change suggests that MTS, after accounting for normal right-left asymmetries, affects the right and left hippocampal surface structure very symmetrically. Preliminary analysis using HDM-LD shows it can predict group classification of MTS and control hippocampi in this well-defined population of patients with MTS and mesial temporal lobe epilepsy (MTLE).

Double-blind comparison of alprazolam, diazepam, and placebo for the treatment of negative schizophrenic symptoms.

Fifty-five schizophrenic outpatients with negative symptoms were treated for up to six weeks by the addition of alprazolam (mean dose, 4.2 mg/d), diazepam (mean dose, 40.4 mg/d), or placebo to their ongoing neuroleptic treatment. A repeated-measures analysis of variance with baseline measurements entered as covariates indicated the presence of a significant time X drug interaction effect for the weekly Brief Psychiatric Rating Scale (BPRS) withdrawal/retardation subfactor scores. During the initial weeks of the study, the alprazolam-treated group had lower scores, while the diazepam-treated group had higher scores than the placebo-treated group. However, an end point analysis performed on the final BPRS withdrawal/retardation subfactor scores showed no significant differences among the three groups, nor were beneficial effects observed on any of the BPRS subfactor scores that assess positive symptoms. Plasma alprazolam levels were maintained throughout the study and ranged from 20 to 100 ng/mL. These results suggest that alprazolam had no sustained significant effect on negative schizophrenic symptoms.

Impulsive aggression in personality disorder correlates with tritiated paroxetine binding in the platelet.

BACKGROUND: To examine the relationship between binding parameters of the platelet central serotonergic (5-HT) transporter and measures of aggression and impulsivity in adult human subjects. METHODS: Maximal number of platelet tritiated paroxetine binding sites (Bmax) and dissociation constant (Kd) values were measured in patients with personality disorder (n = 24) and healthy volunteers (n = 12). Measures of aggression and impulsivity included the total score and aggression subscale of the Life History of Aggression, the Motor Aggression factor and the assault subscale of the Buss-Durkee Hostility Inventory, and the total score and motor impulsivity subscale of the Barratt Impulsiveness Scale. RESULTS: The Bmax, but not Kd, values of platelet tritiated paroxetine binding was inversely correlated with the Life History of Aggression total score and aggression score and with the Buss-Durkee Hostility Inventory assault score in patients with personality disorder but not in healthy volunteer subjects. This relationship was independent of influences of factors related to depression, global function, or history of alcoholism or drug abuse. CONCLUSIONS: Reduced numbers of platelet 5-HT transporter sites may covary with life history of aggressive behavior in patients with personality disorder. This may represent another abnormality in 5-HT function in individuals with personality disorder and aggressive behavior.

Structural magnetic resonance imaging abnormalities in men with severe chronic schizophrenia and an early age at clinical onset.

BACKGROUND: Early age at onset of schizophrenia often signifies a more severe form of the illness. However, the relationship between age at onset and brain abnormalities has not been established. We assessed temporal-limbic morphometry in severely ill men with chronic schizophrenia who had a relatively early onset of illness and examined the relationships among regional brain volumes, clinical symptoms, and age at illness onset. METHOD: Temporal lobe, superior temporal gyrus, hippocampus, temporal horn, lateral ventricles, third ventricle, and frontoparietal volumes were measured on magnetic resonance imaging data from 56 schizophrenic men (mean [SD] age at illness onset, 16.6 [4.2] years) recruited from a state hospital and 52 age- and range-matched healthy control men. RESULTS: Patients had significantly smaller gray matter volumes in the temporal lobe, superior temporal gyrus, and frontoparietal regions; smaller temporal lobe white matter volumes; and larger cerebrospinal fluid volumes for temporal lobe sulci and the 3 ventricular measures. There were no group differences in hippocampal volumes. Psychotic symptom subscores from the Brief Psychiatric Rating Scale were selectively correlated with smaller left posterior superior temporal gyrus gray matter volumes. None of the brain measurements were significantly correlated with age at illness onset. CONCLUSIONS: Data from this unique sample of severely ill schizophrenic men emphasize a pattern of structural abnormalities involving the cortex, but not the hippocampus, in schizophrenia. Furthermore, these data support theories suggesting that superior temporal gyrus abnormalities contribute selectively to psychotic symptoms and that the extent of structural abnormalities is unrelated to age of clinical symptom onset.

Intercorrelations among monoamine metabolite concentrations in human lumbar CSF are not due to a shared acid transport system.

Intercorrelations among homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-hydroxy-phenylglycol (MHPG) concentrations in lumbar cerebrospinal fluid (CSF) were examined before and after blockade of the acid transport system by probenecid in 59 psychiatric inpatients. The three compounds remained intercorrelated despite acid transport blockade, suggesting that the common transport system does not account for their covariance. Other possibilities to explain the interrelationship among these compounds are discussed.

Mesolimbic dopaminergic supersensitivity following electrical kindling of the amygdala.

Limbic seizures developed in rats following daily electrical stimulation of the basolateral nucleus of the amygdala. Animals were designated as "kindled" after five complete (stage 5) behavioral seizures were observed. A subgroup, designated as "superkindled," received three additional weeks of electrical stimulations. Kindled rats were significantly subsensitive to the stereotypy-inducing effects of apomorphine, a direct dopamine agonist, compared to controls. Superkindled rats were supersensitive to the effects of apomorphine. However, both kindled and superkindled rats demonstrated an increase in 3H-spiperone Bmax values, reflecting dopamine D2-receptor densities, in the nucleus accumbens ipsilateral to the stimulating electrode. The number of interictal spikes recorded from the stimulating amygdaloid electrode during the last week of kindling was correlated with changes in apomorphine sensitivity in individual animals.

Limbic/mesolimbic connections and the pathogenesis of schizophrenia.

The development of models of the pathogenesis of neuropsychiatric diseases that build on recent advances in chemical neuroanatomy will help to guide future research. The interconnections among limbic, basal ganglia, and cortical structures are used to form the basis of a hypothesis of the pathogenesis of schizophrenia. The adaptive capacity of subcortical dopamine systems is advanced as an explanation of the many states of the disease.

Symptomatology and cognitive impairment associate independently with post-dexamethasone cortisol concentrations in unmedicated schizophrenic patients.

Serum cortisol concentrations were measured after dexamethasone administration (1 mg) in 21 neuroleptic-free schizophrenic inpatients. Patients were assessed using the Brief Psychiatric Rating Scale and a battery of cognitive tests. A significant correlation was found between negative symptoms and both 8:00 AM and 4:00 PM post-dexamethasone cortisol concentration (PDC). Cognitive impairment on several measures was also correlated with 8 AM PDC, but in an independent manner. Although positive and negative symptoms were unrelated, exploratory analysis revealed a significant inverse correlation between a positive symptom grouping and both 8:00 AM and 4:00 PM PDC.

Possible associations among plasma prolactin levels, tardive dyskinesia, and paranoia in treated male schizophrenics.

To determine whether there is an association between prolactin (PRL) levels and psychopathology or tardive dyskinesia during neuroleptic treatment, we measured plasma prolactin levels and neuroleptic activity (NA) in 33 chronically treated male schizophrenics. Neuroleptic dose, plasma NA, and PRL were significantly intercorrelated. Plasma PRL levels were also measured in 8 male schizophrenics recently withdrawn from neuroleptics and in 18 normal male controls. In treated patients, but not in controls, PRL levels decreased with age and duration of illness, two variables that we interpreted as indirect measures of neuroleptic exposure. PRL levels in patients recently withdrawn from neuroleptics were lower than in treated patients or controls, which was suggestive of rebound hypoprolactinemia. A prolactin index, calculated as the ratio of PRL levels to NA, was inversely correlated with paranoid symptoms and tardive dyskinesia in younger treated patients. These results lead to speculation that tuberoinfundibular dopaminergic supersensitivity develops in chronically treated schizophrenics and that it is associated with nigrostriatal supersensitivity, manifested by tardive dyskinesia, and paranoid symptoms, which may reflect mesolimbic supersensitivity.

Dopaminergic supersensitivity follows ferric chloride-induced limbic seizures.

Injection of ferric chloride (FC) into the left amygdala of rats produced limbic seizures that lasted at least 3 weeks. In addition, FC-injected animals demonstrated motor impairment, decreased protesting vocalizations, and spontaneous stereotypies during a behavioral examination. An increase in apomorphine-induced stereotypies was also noted, and weekly administration of apomorphine for 3 weeks potentiated the increase in stereotypies produced by FC injection. These behavioral changes were associated with changes in postsynaptic dopamine D2 receptors. In animals injected only with FC, an increase in the [3H]-spiperone Bmax in the left nucleus accumbens and an increase in Kd in the right nucleus accumbens were noted. In FC-injected animals challenged weekly with apomorphine for 3 weeks, increases in the [3H]-spiperone Bmax in both amygdalae, the left nucleus accumbens, and the right nucleus caudatus and increases in Kd in the left amygdala and right nucleus accumbens were noted. Severance of the anterior commissure at the time of FC injection reversed most of these changes in behavior and dopamine receptor binding. Possible mechanisms for these changes are discussed, as well as the implications of these results for research on limbic dysfunction and psychopathology.

CSF 5-HIAA, serum cortisol, and age differentially predict vegetative and cognitive symptoms in depression.

Prior studies have shown that both cerebrospinal fluid (CSF) concentrations of 5-hydroxyindolacetic acid (5-HIAA) and serum cortisol levels are related to overall symptom severity in depression. In the present study, 30 unmedicated inpatients meeting Research Diagnostic Criteria (RDC) criteria for depression participated in serum cortisol collection and a lumbar puncture for CSF. A multiple regression evaluated the ability of CSF 5-HIAA, serum cortisol, and age to predict cognitive and vegetative symptom clusters of the Hamilton Rating Scale for Depression. The multiple regression to predict the vegetative symptom cluster was highly significant overall (p = 0.002) and found that age and cortisol but not 5-HIAA predicted vegetative symptoms. The regression to predict the cognitive cluster narrowly missed overall significance (p = 0.06). Both CSF 5-HIAA and serum cortisol predicted cognitive symptoms and 5-HIAA predicted the cognitive cluster more strongly than cortisol. Age did not predict cognitive symptoms. The results suggest a dissociation between serum cortisol levels and CSF 5-HIAA in predicting vegetative and cognitive symptom clusters in depression.

Platelet serotonergic markers and Tridimensional Personality Questionnaire measures in a clinical sample.

A group of patients with major depressive disorder, with and without comorbid obsessive-compulsive disorder, completed the Tridimensional Personality Questionnaire (TPQ). Harm Avoidance scores were found to be high compared to published age-matched norms and to display a significant positive correlation with Hamilton Depression Rating Scale scores. Platelet 125I-lysergic acid diethylamide (125I-LSD) and 3H-paroxetine binding Bmax values were measured to test Cloninger's hypothesis that Harm Avoidance scores would correlate significantly with measures of serotonergic function. A significant inverse correlation was found between Harm Avoidance scores and 125I-LSD Bmax values. Correlations between 3H-paroxetine Bmax values and TPQ scale scores were not significant. These results suggest an alternative view of the literature relating platelet 5-hydroxytryptamine-2a receptors and mood disorders in that the temperament dimension, Harm Avoidance, may explain prior inconsistencies involving links with depression and suicidality.

Platelet serotonin markers and depressive symptomatology.

Dysfunction of brain serotonergic symptoms may be a factor in the mood and behavioral disturbances associated with depression. Platelet serotonin measures represent indirect but easily obtainable indices of brain serotonin function. To examine the specificity of relationships between cognitive and vegetative symptom groupings and platelet serotonin measures, we assessed 35 depressed outpatients using the Hamilton Rating Scale for Depression and collected platelets after a minimum 3-week drug-free period. Platelets were also collected from 14 controls. The results showed that depressed patients had lower platelet serotonin (5-HT) uptake site density values than controls and that 5-HT uptake site density values were inversely correlated with the severity of cognitive symptoms of depression. Platelet 5-HT2 receptor density values were higher in depressed patients than controls, and there was a trend toward a direct correlation between the cognitive symptoms of depression and 5-HT2 receptor density values. Neither platelet measure showed any relationship with the severity of the vegetative symptoms of depression.

Progressive neurodegeneration after intracerebroventricular kainic acid administration in rats: implications for schizophrenia?

BACKGROUND: Intracerebroventricular (ICV) administration of kainic acid to rats produces limbic-cortical neuronal damage that has been compared to the neuropathology of schizophrenia. METHODS: Groups of adult rats were administered ICV kainic acid and then assessed for neuronal loss and the expression of proteins relevant to mechanisms of neuronal damage after one and fourteen days. Neuronal loss was assessed by two-dimensional cell counting and protein expression was assessed by immunohistochemistry. RESULTS: ICV kainic acid administration was associated with both immediate (day 1) and delayed (day 14) neuronal loss in the dorsal hippocampus. The immediate injury was largely limited to the CA3 hippocampal subfield, while the delayed injury included the CA1 subfield. Multiple mechanisms of cell death appeared to be involved in the delayed neuronal loss, as evidenced by changes in the expression of glutamate receptor subunits, heat shock protein and jun protein. CONCLUSIONS: ICV kainic acid administration to adult rats produces progressive damage to limbic-cortical neurons, involving both fast and slow mechanisms of cell death. Given the evidence for clinical deterioration, cognitive deficits and hippocampal neuropathy in some cases of schizophrenia, this animal model may be relevant for hypotheses regarding mechanisms of neurodegeneration in that disorder.

Cerebrospinal fluid glutamate inversely correlates with positive symptom severity in unmedicated male schizophrenic/schizoaffective patients.

BACKGROUND: Recent hypotheses have suggested that diminished brain glutamate may be of importance in the neurochemical basis of schizophrenia. METHODS: We assayed cerebrospinal fluid for glutamate and obtained clinical symptom ratings in 19 medication-free (except p.r.n. chloral hydrate) schizophrenic or schizoaffective (typically with significant schizophrenic qualities) male inpatients. RESULTS: Ratings of positive symptoms were significantly inversely correlated (rs = -.457, p < .05, one-tailed test) with glutamate concentrations. Hallucinatory behavior was strongly correlated (rs = -.621, p < .01, one-tailed test) with glutamate. A subset of 11 patients consented to a second lumbar puncture (LP) after treatment with haloperidol (typically 15 or 20 mg/day) for 2-4 weeks. Haloperidol treatment did not alter glutamate concentrations. No correlations were noted between glutamate and symptoms in the medicated subsample. Though approximately half the patients received chloral hydrate during the 72 hours prior to the unmedicated LP, the correlations between positive symptoms and glutamate in the patients who received no chloral hydrate prior to the LP were quite similar to those found in the overall sample. CONCLUSIONS: The results provide further support for the potential importance of glutamate in the neurochemical basis of schizophrenia.

ERPs in schizophrenia: effects of antipsychotic medication.

Thirty unmedicated schizophrenics were compared to 29 age-matched controls on auditory and visual event-related brain potential (ERP) paradigms. Twenty-one of these patients were tested again after 1 week on placebo and after 4 weeks on antipsychotic medication. Before treatment, N1, N2, and P3 components of the auditory ERP were smaller in the schizophrenics than in the controls. Although visual N2 was smaller in schizophrenics, visual P3 was not. In spite of significant clinical improvement with antipsychotic treatment, amplitudes of auditory and visual N1, N2, and P3 were not significantly changed. Higher blood levels of antipsychotic medication were related to reductions in auditory P3 latency, however. In addition, higher levels of cerebrospinal fluid (CSF) MHPG (methoxyhydroxyphenylglycol) were associated with larger auditory N1s and larger auditory and visual P3s, suggesting an influence of arousal on these components in schizophrenics. In spite of this influence, reduction of the auditory P3 in schizophrenia is an enduring trait of the disease, which is not affected by antipsychotic medication or clinical improvement.