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J E Kleinman

Publications and source records attributed to J E Kleinman.

At least 37 records · Page 2Linked to original sources
PubMed2001

A comparison of verbal fluency tasks in schizophrenic patients and normal controls.

Previous studies have reported significant impairment on verbal fluency tasks (semantic and letter) among schizophrenic subjects. However, the possibility of specific categorical deficits has not been adequately investigated. Nor have the effects of task duration, the stability between testing sessions, and the relationship between intelligence and performance on fluency been thoroughly studied. We performed a series of 3 min fluency tasks (semantic/syntactic and letter) to determine whether duration specific or category-specific differences exist between schizophrenic subjects and normal controls. Each subject was tested at three different times as a means of estimating word pool and assessing the stability of fluency output. Subjects were asked to generate exemplars from each of four semantic/syntactic categories (animals, tools, common nouns and verbs) and three letters (G, E and T). Data from 13 schizophrenic subjects and 15 sex-, age- and pre-morbid-IQ-matched control subjects revealed that patients' overall performance on both the semantic and letter fluency tasks was impaired. While differential impairment on specific semantic categories was noted between groups, no differential effects relating to task duration or testing session were present. Further, by comparing the number of novel words produced in the three testing sessions, we found the groups to be equivalent, a finding we take to suggest that schizophrenic patients' lexicon is intact. Covarying current IQ eliminated the group difference robustly for letter fluency, while only marginally for semantic fluency. Our data revealed the presence of impairment in semantic and letter fluency tasks in schizophrenic patients consistent with previous reports, and also that patients were differentially impaired on semantic categories.

Adult↗
PubMed2001

A quantitative immunohistochemical study of astrocytes in the entorhinal cortex in schizophrenia, bipolar disorder and major depression: absence of significant astrocytosis.

A number of macroscopic changes have been reported in the temporal lobe in schizophrenia. We have evaluated the density of glial fibrillary acidic protein (GFAP)-positive astrocytes in cortical layers 2 through 6 in the intermediate subarea of entorhinal cortex in two cohorts: the first, 15 cases, made up of schizophrenic (n = 7) and normal nonpsychiatric control subjects (n = 8), and the second, 56 cases, composed of schizophrenic (n = 14), bipolar disorder (n = 13), major depressive (n = 14) and normal control subjects (n = 15). No significant difference in density of GFAP-positive astrocytes was detected between the psychiatric diagnostic groups and the normal controls in either of the two cohorts. In both cohorts there was a positive correlation between increasing age and astrocytic density which reached statistical significance in only the larger cohort (r = 0.38, p = 0.004). Our results find no evidence for astrocytosis in the entorhinal cortex in several mental illnesses. Although other studies have reported macroscopic and other structural abnormalities in this region, we have not detected astrocytic proliferation, which is a typical hallmark of atrophy and/or progressive neuronal loss.

Adult↗
PubMed2001

Synaptophysin and GAP-43 mRNA levels in the hippocampus of subjects with schizophrenia.

Synaptophysin and growth associated protein-43 (GAP-43) are synaptic proteins colocalized to the presynaptic terminal, and involved in regulating transmitter release and synaptic plasticity. Recent studies have proposed an alteration in the number of synapses in the brains of individuals with schizophrenia. As a corollary, we hypothesized that there may be an alteration in the level of mRNAs that code for synaptic proteins in brains of patients with schizophrenia. Using in situ hybridization, we investigated the levels of synaptophysin and GAP-43 mRNA in the medial temporal lobe of 10 normal subjects, 11 subjects with schizophrenia and 10 psychiatric control subjects. Synaptophysin mRNA levels were significantly reduced in several hippocampal subfields in both the schizophrenic and psychiatric control groups. GAP-43 mRNA levels were not significantly reduced in either group. The implications of these findings are discussed in relation to neuroleptic treatment and the pathophysiology of mental illness.

Adult↗
PubMed2001

Reduced GAP-43 mRNA in dorsolateral prefrontal cortex of patients with schizophrenia.

Schizophrenia has been associated with anatomical and functional abnormalities of the dorsolateral prefrontal cortex (DLPFC), which may reflect abnormal connections of DLPFC neurons. We measured mRNA levels of growth-associated protein (GAP-43), a peptide linked to the modifiability of neuronal connections, in post-mortem brain tissue from two cohorts of patients with schizophrenia and controls. Using the RNase protection assay (RPA), we found a significant reduction in GAP-43 mRNA in the DLPFC, but not in the hippocampus, of patients with schizophrenia. With in situ hybridization histo- chemistry (ISHH), performed on a separate cohort, we confirmed the reduction of GAP-43 mRNA in the DLPFC of patients with schizophrenia. We detected reduced GAP-43 mRNA per neuron in layers III, V and VI of patients with schizophrenia compared with normal controls and patients with bipolar disorder. Thus, glutamate neurons in DLPFC of schizophrenic patients may synthesize less GAP-43, which could reflect fewer and/or less modifiable connections than those in normal human brain, and which may be consistent with the deficits of prefrontal cortical function that characterize schizophrenia.

Adult↗
PubMed2000

Neuropathology of bipolar disorder.

The literature on the neuropathology of bipolar disorder (BD) is reviewed. Postmortem findings in the areas of pathomorphology, signal transduction, neuropeptides, neurotransmitters, cell adhesion molecules, and synaptic proteins are considered. Decreased glial numbers and density in both BD and major depressive disorder (MDD) have been reported, whereas cortical neuron counts were not different in BD (in Brodmann's areas [BAs] 9 and 24). In contrast, MDD patients showed reductions in neuronal size and density (BA 9, BA 47). There are a number of findings of alterations in neuropeptides and monoamines in BD brains. Norepinephrine turnover was increased in several cortical regions and thalamus, whereas the serotonin metabolite, 5-hydroxyindoleacetic acid, and the serotonin transporter were reduced in the cortex. Several reports further implicated both cyclic adenosine monophosphate and phosphatidylinositol (PI) cascade abnormalities. G protein concentrations and activity increases were found in the occipital, prefrontal, and temporal cortices in BD. In the PI signal cascade, alterations in PKC activity were found in the prefrontal cortex. In the occipital cortex, PI hydrolysis was decreased. Two isoforms of the neural cell adhesion molecules were increased in the hippocampus of BD, whereas the synaptic protein marker, synaptophysin, was not changed. The findings of glial reduction, excess signal activity, neuropeptide abnormalities, and monoamine alterations suggest distinct imbalances in neurochemical regulation. Possible alterations in pathways involving ascending projections from the brain stem are considered. Larger numbers of BD brains are needed to further refine the conceptual models that have been proposed, and to develop coherent models of the pathophysiology of BD.

Autopsy↗
PubMed2000

Localization of epidermal growth factor receptors and putative neuroblasts in human subependymal zone.

Studies in rodents and monkeys suggest that neuronal precursor cells continue to exist and differentiate well into adulthood in these species. These results challenge the long held assumption that neurogenesis does not occur in the postnatal human brain. We examined the rostral subependymal zone (SEZ) of postnatal human brain for expression of cell phenotypic markers that have been associated with neuronal precursors and neuroblasts in rodent brain. We found epidermal growth factor receptor (EGF-R) mRNA and protein to be expressed in infant, teen, young adult, and adult human SEZ. Some SEZ cells expressed the polysialic acid form of neural cell adhesion molecule (PSA-NCAM), characteristic of migrating neuroblasts, as well as class III beta-tubulin and Hu protein, characteristic of neuroblasts and early neurons. These neuroblast-like cells were negative for glial fibrillary acidic protein (GFAP), 2;,3;-cyclic nucleotide 3;-phosphohydrolase (CNPase), and vimentin, suggesting that they were not differentiating as glia. Our results show that neuroblast-like cells exist in the human SEZ and support the theory that SEZ of postnatal human brain has neurogenic potential.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2000

Trinucleotide repeat expansion in the beta1 subunit of the sodium pump in manic-depression illness: a negative study.

BACKGROUND: Trinucleotide repeats have become a recognized molecular abnormality in a variety of neuropsychiatric conditions. Bipolar illness has been purported to be a possible trinucleotide repeat-associated disease. Since abnormalities in the expression and regulation of the sodium- and potassium-activated adenosine triphosphatase (Na,K-ATPase) have been documented in bipolar patients and since the beta1 subunit of this pump contains a heterogenous GCC repeat, we decided to investigate the possibility of a repeat expansion in beta1 subunit of Na,K-ATPase in bipolar patients. METHODS: DNA from postmortem temporal cerebral cortex tissue of five bipolar subjects and five matched normal controls and five lyumphoblastoid cells lines from the Old Order Amish bipolar pedigrees and match normal controls were used for this study. The GCC rich region of beta1 DNA was amplified by polymerase chain reaction (PCR) and sequenced. RESULTS: The range of GCC repeat in the beta1 gene is between 7 and 9 in our population. This is not different in bipolar patients from normal controls. LIMITATIONS: This study examined a small number of patients and examined a very limited portion of the locus. CONCLUSION: It appears that there is not an expansion of the GCC repeat in the beta1 gene in bipolar patients.

Adult↗
PubMed1999

Differential effects of haloperidol and clozapine on ionotropic glutamate receptors in rats.

Despite multiple lines of investigation the effect of neuroleptics on glutamate-mediated neurotransmission remains controversial. To study the effects of typical and atypical neuroleptics on selected parameters of glutamate-mediated neurotransmission, male Sprague-Dawley rats were randomly assigned to a 21-day oral treatment course with vehicle, haloperidol (HDL), or clozapine (CLZ). Coronal slices of rat brain were then incubated with tritiated ligands to measure NMDA, AMPA, and kainate receptor, and glutamate reuptake site density. Regions of interest included the frontal cortex, anterior cingulate cortex, dorsal striatum, ventral striatum, and the nucleus accumbens. CLZ increased the density of AMPA receptors significantly in the frontal and anterior cingulate cortices compared with normal controls. In the dorsal and ventral striatum, and nucleus accumbens as a whole, CLZ-treated rats had a higher AMPA receptor density compared with both the HDL- and vehicle-treated controls. Additionally, within the nucleus accumbens, CLZ-treated rats had a higher density of AMPA receptors compared with the HDL group in the core, and at trend level in the shell. There was a group by region interaction for NMDA receptor density, primarily reflecting the tendency of HDL treated rats to have high receptor densities in the frontal and anterior cingulate cortices. Kainate receptors and glutamate reuptake site densities did not differ significantly across groups. These results suggest a critical role for glutamate in the mediation of atypical antipsychotic drug action in anatomically-specific regions, and further encourage the investigation of glutamate neurotransmitter systems in schizophrenia.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1999

Evaluation of superior vermal Purkinje cell placement in mental illness.

BACKGROUND: A number of neuroimaging and neuropathological studies have reported abnormalities in the cerebellar vermis in schizophrenia and bipolar disorder. In an effort to further understand vermal abnormalities in mental illness, we have analyzed ectopic placement of Purkinje-like cells. METHODS: The superior cerebellar vermis was evaluated in 39 cases of severe mental illness [schizophrenia (n = 12), bipolar disease (n = 12), and depression (n = 15)]. We also examined 9 subjects with polysubstance abuse and 15 normal controls. All normally placed Purkinje cells and displaced Purkinje-like cells (i.e., in the internal granule layer and intrafoliar white matter) were counted in the same foliar field. The ratio of displaced Purkinje-like cells to total Purkinje cells and Purkinje cell density were calculated. RESULTS: No significant difference in the ratio of displaced to normally placed Purkinje cells or in Purkinje cell density between groups of subjects was found. CONCLUSIONS: Our study does not support a hypothesis of abnormalities of Purkinje cell migration or other events related to their displacement as a basis for the vermal abnormalities reported previously in schizophrenia and bipolar disorder.

Adult↗
PubMed1999

Evidence for a deficit in cholinergic interneurons in the striatum in schizophrenia.

Neurochemical and functional abnormalities of the striatum have been reported in schizophrenic brains, but the cellular substrates of these changes are not known. We hypothesized that schizophrenia may involve an abnormality in one of the key modulators of striatal output, the cholinergic interneuron. We measured the densities of cholinergic neurons in the striatum in schizophrenic and control brains in a blind analysis, using as a marker of this cell population immunoreactivity for choline acetyltransferase, the synthetic enzyme of acetylcholine. As an independent marker, we used immunoreactivity for calretinin, a protein which is co-localized with choline acetyltransferase in virtually all of the cholinergic interneurons of the striatum. A significant decrease in choline acetyltransferase-positive and calretinin-positive cell densities was found in the schizophrenic cases compared with controls in the striatum as a whole [for the choline acetyltransferase-positive cells: controls: 3.21 +/- 0.48 cells/mm2 (mean +/- S.D.), schizophrenics: 2.43 +/- 0.68 cells(mm2; P < 0.02]. The decrease was patchy in nature and most prominent in the ventral striatum (for the choline acetyltransferase-positive cells: controls: 3.47 +/- 0.59 cells/mm2, schizophrenics: 2.52 +/- 0.64 cells/ mm2; P < 0.005) which included the ventral caudate nucleus and nucleus accumbens region. Three of the schizophrenic cases with the lowest densities of cholinergic neurons had not been treated with neuroleptics for periods from more than a month to more than 20 years. A decrease in the number or function of the cholinergic interneurons of the striatum may disrupt activity in the ventral striatal-pallidal-thalamic-prefrontal cortex pathway and thereby contribute to abnormalities in function of the prefrontal cortex in schizophrenia.

Adult↗
PubMed1999

Alterations of hippocampal secreted N-CAM in bipolar disorder and synaptophysin in schizophrenia.

Schizophrenia and bipolar disorder have both been linked to structural abnormalities of the hippocampus, which is consistent with a neurodevelopmental anomaly. One isoform of the neural cell adhesion molecule (N-CAM) protein, cytosolic N-CAM 105-115 kDa, was previously shown to be increased in schizophrenia in the hippocampus and prefrontal cortex. Another isoform of N-CAM, the variable alternative spliced exon of N-CAM, was also increased in the hippocampus and prefrontal cortex of bipolar disorder patients. In the present study, the secreted isoform of N-CAM (SEC N-CAM), synaptophysin, and actin proteins were measured in the hippocampus of controls, suicide victims, and patients with bipolar disorder or schizophrenia by quantitative Western immunoblotting. Previous measurements of cytosolic N-CAM (105-115 kDa) protein, from the same hippocampus samples, were used to calculate the N-CAM (105-115 kDa)/synaptophysin ratio. An affinity purified antibody to SEC N-CAM recognized SEC N-CAM (108 kDa and 115 kDa) in brain but SEC N-CAM was not detectable in CSF. In bipolar disorder, but not in schizophrenia, an increased SEC N-CAM 115 kDa/108 kDa ratio was found as compared to controls (P = 0.03). The synaptophysin/actin ratio was significantly decreased in schizophrenia (P = 0.014) as compared to controls. The cytosolic N-CAM 105-115 kDa/synaptophysin ratio was increased in patients with schizophrenia (P= 0.017), but not in bipolar disorder. Thus, bipolar disorder patients show altered expression of SEC N-CAM in the hippocampus. Patients with schizophrenia show a decrease in synaptophysin and an increase in the cytosolic N-CAM 105-115 kDa/synaptophysin ratio. The results offer further evidence of differences in protein expression between bipolar disorder and schizophrenia in the hippocampus, which is consistent with a distinct neuropathology for each neuropsychiatric disorder.

Actins↗
PubMed1999

Expression of the myristoylated alanine-rich C kinase substrate (MARCKS) and MARCKS-related protein (MRP) in the prefrontal cortex and hippocampus of suicide victims.

BACKGROUND: Although suicide is a leading cause of death in the United States and represents a significant public health threat, little is known about the neurobiological or molecular factors that contribute to its pathophysiology. A number of studies now indicate that lithium has considerable efficacy in the prevention of suicide in patients with affective disorders, and accumulating evidence indicates that protein kinase C (PKC) and its substrates, in particular the myristoylated alanine-rich C kinase substrate (MARCKS), are primary targets of chronic lithium treatment. We therefore hypothesized that a dysregulation in MARCKS expression in key brain regions could contribute to the pathophysiology associated with suicide. To address this, we examined MARCKS, as well as the closely related MARCKS-related protein (MRP), mRNA expression in the hippocampus and dorsolateral prefrontal cortex of suicide victims and normal controls. METHOD: MARCKS and MRP mRNA expression was assessed by quantitative in situ hybridization histochemistry performed on postmortem hippocampal and dorsolateral prefrontal cortex sections from suicide (N = 9) and normal control (N = 10) brains. RESULTS: In the normal hippocampus, both MARCKS and MRP mRNA expression were highest in the granule cell layer and low-moderate in CA1, CA3, and hilus. A high level of MRP mRNA expression was also observed in the white matter of the fimbria/fornix. Neither MARCKS nor MRP mRNA expression levels differed significantly in the granule cell layer, CA3, hilus, or CA1 in suicide victims relative to normal controls (1-way ANOVA, p > .05). In the normal prefrontal cortex, MARCKS was expressed exclusively in gray matter (layers I-VI), whereas MRP was expressed in both gray and white matter. Neither MARCKS nor MRP mRNA expression levels in the gray and white matter regions of the dorsal prefrontal cortex differed between suicides and normal controls (1-way ANOVA, p > .05). CONCLUSION: The present findings are the first to demonstrate the expression and distribution of MARCKS and MRP in the human hippocampus and dorsolateral prefrontal cortex, and their expression pattern within these regions bears strong resemblance to those observed in the adult rat brain. Comparison of MARCKS and MRP mRNA expression in the hippocampus and prefrontal cortex of suicide victims and normal controls indicates that these 2 mRNAs are not differentially regulated in these regions. However, differences in MARCKS and MRP protein expression and function cannot be ruled out by the present findings.

Adult↗
PubMed1998

Alpha 2 isoform of the Na,K-adenosine triphosphatase is reduced in temporal cortex of bipolar individuals.

BACKGROUND: The pathophysiology of bipolar illness has been associated with changes in transmembrane ion flux and redistribution of biologically active ions. The recent identification of multiple isoforms of Na,K-adenosine triphosphatase (ATPase) alpha and beta subunits raises the possibility of altered pump isoform expression. METHODS: We determined Na,K-ATPase alpha subunit expression in postmortem temporal cortex gray matter from individuals suffering from bipolar disorder, schizoaffective disorder, schizophrenia, and matched normal controls. Quantification of isoform expression was accomplished via densitometric scanning of Western blots utilizing isoform-specific antibodies. RESULTS: Bipolar individuals exhibited a significant reduction in the abundance of the alpha 2 isoform of Na,K-ATPase compared to normal controls. Schizophrenic and schizo-affective brains were not significantly different from normal controls. CONCLUSION: These data suggest that previously observed abnormalities in regulation and distribution of ions in bipolar illness may be related to specific alpha 2 dysregulation.

Bipolar Disorder↗
PubMed1998

Abnormal expression of cell recognition molecules in schizophrenia.

Schizophrenia is a neuropsychiatric disorder of unknown etiology associated with subtle changes in brain morphology. The cell recognition molecules (CRMs) neural cell adhesion molecule (N-CAM) and L1 are involved in morphoregulatory events and numerous neurodevelopmental processes. We found a selective increase of 105- to 115-kDa N-CAM in the hippocampus and prefrontal cortex of patients with schizophrenia while other N-CAM isoforms and L1 proteins were not altered. There was also evidence for an abnormality in CRM expression in schizophrenic patients: concentrations of 200-kDa L1 were strongly correlated with expression of N-CAM isoforms and cleaved L1 proteins in controls, whereas these correlations were absent in patients with schizophrenia. The increase of the 105- to 115-kDa N-CAM isoform in the brains of patients with schizophrenia confirms previous cerebrospinal fluid findings. Increased N-CAM in schizophrenia may result from structural brain abnormalities, from glial processing of N-CAM, or from an aberration in the regulation of N-CAM expression.

Bipolar Disorder↗
PubMed1998

VASE-containing N-CAM isoforms are increased in the hippocampus in bipolar disorder but not schizophrenia.

The neural cell adhesion molecule (N-CAM) is a cell recognition molecule that is involved in cellular migration, synaptic plasticity, and CNS development. In schizophrenia, a 105- to 115-kDa N-CAM protein is increased in CSF and in the hippocampus and prefrontal cortex. The variable alternatively spliced exon (VASE) of N-CAM is developmentally regulated and can be spliced into any of the major 120-, 140-, and 180-kDa N-CAM isoforms. We determined that the variable alternative spliced exon of N-CAM (VASE) also is increased in bipolar disorder by quantitative Western immunoblot. VASE immunoreactive proteins (triplet bands around 140 kDa and a single band around 145 kDa) were identified in soluble and membrane brain extracts and quantified in the hippocampus. Soluble VASE 140 kDa was increased in the hippocampus of patients with bipolar disorder as compared to controls, patients with schizophrenia, and suicide cases. Membrane-extracted VASE 140 and 145 kDa were unchanged in the same groups. Multiple 145-kDa VASE-immunoreactive proteins that also reacted to an N-CAM antibody were separated by isoelectric focusing and electrophoresis followed by western immunoblotting; however, the VASE 140-kDa proteins were only weakly N-CAM immunoreactive. By immunohistochemistry, VASE colocalized with GFAP-positive astrocytes in the hippocampus. VASE immunostaining was also observed in the cytoplasm of CA4 pyramidal neurons that were positive for phosphorylated high molecular weight neurofilament and synaptophysin terminals. Thus no differences in VASE were found in patients with schizophrenia, but there was a marked increase of VASE immunoreactive proteins in bipolar disorder. It is possible that abnormal regulation of N-CAM proteins results in differing patterns of abnormal expression in neuropsychiatric disorders.

Bipolar Disorder↗
PubMed1998

The neuroanatomy and neurochemistry of schizophrenia.

Substantial progress, in part owing to recent refinements in methodology, has been made in unraveling the anatomic correlates of schizophrenia. Subtle pathomorphologic changes, distinct from those of well-known degenerative brain disorders, have been observed. Neurochemical characterization has illuminated the nature of these morphologic abnormalities and has pointed to complex dysregulation of neurotransmitters and G proteins. New biochemical hypotheses such as the glutamate hypothesis have replaced and revitalized more established concepts in the neurochemistry of schizophrenia.

Brain↗
PubMed1997

Neuropathology of suicide. A review and an approach.

Neuropathology is one approach to the effort to elucidate the pathophysiology of suicide. Initial neurochemical studies focusing on the roles of serotonin (5-HT) and noradrenaline (NE) abnormalities in brains of suicide victims have been somewhat inconsistent. More recently developed methodologies, including quantitative receptor autoradiography, immunoblotting, immunohistochemistry, cell morphometry, in situ hybridization, Northern analysis, solution hybridization/RNase protection assay, reverse transcriptase polymerase chain reaction, and genotyping, which have already been applied successfully in studies of other disorders of brain structure or function, are now increasingly being adopted for postmortem studies of suicide. These new strategies are adding convergent evidence for brain 5-HT and NE dysfunction in the etiology of suicide susceptibility, refining the neuroanatomical localization of this dysfunction, and in addition, implicating heretofore unsuspected candidate neurotransmitter systems in the neuropathological substrates of suicide susceptibility. It is argued here that the confluence of the availability of suitable postmortem samples and this augmentation of our armamentarium of techniques promises the attainment of important new insights into the biological underpinnings of suicide from postmortem research. It is to be hoped that this new knowledge might inspire novel pharmacotherapeutic strategies for the prevention of suicide.

Brain↗