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Biomedical subjects

Carol A Tamminga

Publications and source records attributed to Carol A Tamminga.

At least 19 recordsLinked to original sources
PubMed2006

Human postmortem tissue: what quality markers matter?

Postmortem human brain tissue is used for the study of many different brain diseases. A key factor in conducting postmortem research is the quality of the tissue. Unlike animal tissue, whose condition at death can be controlled and influenced, human tissue can only be collected naturalistically. This introduces potential confounds, based both on pre- and postmortem conditions, that may influence the quality of tissue and its ability to yield accurate results. The traditionally recognized confounds that reduce tissue quality are agonal factors (e.g., coma, hypoxia, hyperpyrexia at the time of death), and long postmortem interval (PMI). We measured tissue quality parameters in over 100 postmortem cases collected from different sources and correlated them with RNA quality (as indicated by the RNA Integrity Number (RIN)) and with protein quality (as measured by the level of representative proteins). Our results show that the most sensible indicator of tissue quality is RIN and that there is a good correlation between RIN and the pH. No correlation developed between protein levels and the aforementioned factors. Moreover, even when RNA was degraded, the protein levels remained stable. However, these correlations did not prove true under all circumstances (e.g., thawed tissue, surgical tissue), that yielded unexpected quality indicators. These data also suggest that cases whose source was a Medical Examiner's office represent high tissue quality.

Adult↗
PubMed2006

Phosphorylation of the tubulin-binding protein, stathmin, by Cdk5 and MAP kinases in the brain.

Regulation of cytoskeletal dynamics is essential to neuronal plasticity during development and adulthood. Dysregulation of these mechanisms may contribute to neuropsychiatric and neurodegenerative diseases. The neuronal protein kinase, cyclin-dependent kinase 5 (Cdk5), is involved in multiple aspects of neuronal function, including regulation of cytoskeleton. A neuroproteomic search identified the tubulin-binding protein, stathmin, as a novel Cdk5 substrate. Stathmin was phosphorylated by Cdk5 in vitro at Ser25 and Ser38, previously identified as mitogen-activated protein kinase (MAPK) and p38 MAPKdelta sites. Cdk5 predominantly phosphorylated Ser38, while MAPK and p38 MAPKdelta predominantly phosphorylated Ser25. Stathmin was phosphorylated at both sites in mouse brain, with higher levels in cortex and striatum. Cdk5 knockout mice exhibited decreased phospho-Ser38 levels. During development, phospho-Ser25 and -Ser38 levels peaked at post-natal day 7, followed by reduction in total stathmin. Inhibition of protein phosphatases in striatal slices caused an increase in phospho-Ser25 and a decrease in total stathmin. Interestingly, the prefrontal cortex of schizophrenic patients had increased phospho-Ser25 levels. In contrast, total and phospho-Ser25 stoichiometries were decreased in the hippocampus of Alzheimer's patients. Thus, microtubule regulatory mechanisms involving the phosphorylation of stathmin may contribute to developmental synaptic pruning and structural plasticity, and may be involved in neuropsychiatric and neurodegenerative disorders.

Animals↗
PubMed2006

Insight and frontal cortical function in schizophrenia: a review.

Insight into illness has been identified as a clinically important phenomenon, in no small part due to an association with treatment-adherence. An increasing number of studies, but not all, have observed poor insight to be a reflection of cognitive dysfunction in schizophrenia. A review of 34 published English-language studies found a significant number (i.e., 21) reporting a relationship between insight deficits and impaired performance on cognitive tasks primarily mediated by frontal cortex. A significant number of reviewed studies examined insight function in more than one psychiatric population, including bipolar and schizoaffective disorder. The most replicated findings from these studies were the correlations between insight deficits and impaired performance on the Wisconsin Card Sorting Test (WCST). More specifically, WCST perseverative errors correlated positively and the number of categories completed correlated negatively with poor insight, suggesting that impaired insight may be mediated by deficiencies in conceptual organization and flexibility in abstract thinking. Since the WCST requires the ability to demonstrate conceptual flexibility through the generation, maintenance and switching of mental sets along with the capacity to use verbal feedback to correct errors, it would appear that such 'executive' functions are most related to insight. In addition, recently identified structural correlates of poor insight in schizophrenia show some association with anosognosia in neurological patients. This review will discuss the implications of these findings and directions for future research.

Databases, Factual↗
PubMed2006

Regional alterations in RGS4 protein in schizophrenia.

The regulator of G protein signaling (RGS) molecules are a class of proteins that modulate the signaling activity of G-protein coupled receptors. Regulator of G protein signaling 4 (RGS4) is of particular interest in schizophrenia since it is associated with the dopamine (DA) receptor, its expression is altered in affected CNS tissue, and polymorphisms in the RGS4 gene are being examined as risk factors for the disease (Morris et al.2004, Am J Med Genet B Neuropsychiatr Genet 125:50-53; Prasad et al.2005, Mol Psychiatry 10:213-219; Williams et al.2004, Biol Psychiatry 55:192-195). To further test for the involvement of RGS4 expression in schizophrenia, we examined a selection of different cortical and subcortical regions in human brain for alterations in RGS4 mRNA and protein expression. To evaluate the effect of antipsychotic medication on RGS4 expression levels, we compared a subset of treated and untreated cases that were off antipsychotic medication for at least 3 months prior to death. We report a significant decrease in RGS4 mRNA levels in the cingulate gyrus, superior frontal gyrus, and the insular cortex of all schizophrenia cases when compared with controls. A decrease in RGS4 mRNA was also observed in the caudate, but only in the medicated schizophrenia cases. Measurement of protein levels using Western blot demonstrated that RGS4 protein is decreased in the frontal cortex of schizophrenia cases.

Adult↗
PubMed2006

Correlations between rCBF and symptoms in two independent cohorts of drug-free patients with schizophrenia.

We report on the correlations between whole brain rCBF and the positive and negative symptoms of schizophrenia in two cohorts of patients who were scanned while free of antipsychotic medication. We hypothesized that positive symptoms would correlate with rCBF in limbic and paralimbic regions, and that negative symptoms would correlate with rCBF in frontal and parietal regions. Both cohorts of patients with schizophrenia (Cohort 1: n=32; Cohort 2: n=23) were scanned using PET with H(2)(15)O while free of antipsychotic medication for an average of 21 and 15 days, respectively. Both groups were scanned during a resting state. Using SPM99, we conducted pixel by pixel linear regression analyses between BPRS scores and whole brain rCBF. As hypothesized, positive symptoms correlated with rCBF in the anterior cingulate cortex (ACC) in a positive direction and with the hippocampus/parahippocampus in a negative direction in both patient groups. When the positive symptoms were further divided into disorganization and hallucination/delusion scores, similar positive correlations with ACC and negative correlations with hippocampus rCBF were found. In both cohorts, the disorganization scores correlated positively with rCBF in Broca's area. As expected, negative symptoms correlated inversely with rCBF in frontal and parietal regions. This study provides evidence that limbic dysfunction may underlie the production of positive symptoms. It suggests that abnormal function of Broca's area may add a specific language-related dimension to positive symptoms. This study also provides further support for an independent neurobiological substrate of negative symptoms distinct from positive symptoms. The involvement of both frontal and parietal regions is implicated in the pathophysiology of negative symptoms.

Adolescent↗
PubMed2006

Switch or stay?

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Antipsychotic Agents↗
PubMed2006

HIV and AIDS.

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AIDS Dementia Complex↗
PubMed2006

The neurobiology of cognition in schizophrenia.

Currently, no drugs exist that effectively treat cognition in people with schizophrenia. What is known about the neurobiology of cognition in schizophrenia is derived from the animal literature; it is inadequate and superficial. Despite this lack, pharmacologic research into potential molecular targets has uncovered several viable possibilities from animal studies. A subcommittee of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) program investigated the range of putative molecular targets for treating cognition. Those targets that show promise for pharmacologic focus include the dopamine receptors (especially D1) in the prefrontal cortex (PFC), the serotonin receptors in the PFC and anterior cingulate cortex, the glutamatergic excitatory synapse, the acetylcholine nicotinic receptors in the hippocampus, the acetylcholine muscarinic receptors, and the brain gamma-aminobutyric acid (GABA) system. Once developed and tested, the effective compounds will be valuable for the treatment of the symptom domains of cognitive dysfunction and negative symptoms.

Animals↗
PubMed2006

The neurobiology of cognition in schizophrenia.

Cognitive dysfunction in schizophrenia differs from cognitive dysfunction in neurodegenerative illnesses because it is associated with neuronal dysfunction and not neurodegeneration. Pharmacologically, potential targets for developing treatments may differ from cognition in dementing disorders. Several putative molecular targets for treating cognition in schizophrenia show promise, such as treatments that act on the D(1) receptor of the dopamine system; the 5HT(1A), 5HT(2A), and 5HT(6), receptors of the serotonin system; and ampakines, Glycine/D-cycloserine, D-serine, and mGluR 2/3 agonists of the glutamatergic system. Other receptors associated with improvement in cognition include nicotinic and muscarinic receptors, and the alphalpha2 subunit receptor of the brain GABA system. Domain treatment of schizophrenia is a new method of treating schizophrenia that involves treating a single domain of dysfunction at a time.

Animals↗
PubMed2005

Multidose risperidone treatment evaluated in a rodent model of tardive dyskinesia.

Risperidone is a second-generation antipsychotic that lacks acute motor side effects at low doses (<6 mg/day), but above this level is associated with parkinsonism and akathesia. The literature suggests an association between acute motor side effects and tardive dyskinesia (TD); therefore, we hypothesized that low dose levels of risperidone will spare TD. As clinical studies of TD liability with fixed doses of risperidone are difficult to conduct, we tested low and high doses of risperidone in a rodent model of TD, vacuous chewing movements (VCMs) production. Low doses of risperidone (1.5 mg/kg/day) resulted in control levels of VCMs after 6 months of treatment, whereas high doses of risperidone (6 mg/kg/day) produced VCM in the same range as haloperidol. Plasma drug levels are reported. If this animal model predicts TD risk in humans, the TD liability with low-dose risperidone is at a placebo level, whereas higher doses show haloperidol-like TD risk, as predicted from the acute motor effects.

Animals↗
PubMed2005

Functional effects of single dose first- and second-generation antipsychotic administration in subjects with schizophrenia.

Using PET with (15)O water, we characterized the time course of functional brain changes following the acute administration of a first- and a second-generation antipsychotic. Volunteers with schizophrenia were scanned while drug-free (baseline) and after single dose administration of haloperidol (n=6) or olanzapine (n=6) during a time course adapted to their plasma kinetics. To obtain brain location information, we contrasted each post-drug scan to baseline-acquired scans. We plotted the regional cerebral blood flow (rCBF) extracted in these locations and calculated the kinetic characteristics of the curves. Further, we compared and contrasted the rCBF changes induced by the drugs over the first 4 h post-drug administration. Dorsal and ventral striatum, thalamus and anterior cingulate cortex were activated with haloperidol, while frontal, temporal and cerebellum regions evidenced reduced flow. With olanzapine, ventral striatum, anterior cingulate and temporal cortices evidenced increases, and thalamus and lingual cortex decreases, in rCBF. Both drugs activated the caudate nucleus. Haloperidol induced greater activation of the dorsal striatum than did olanzapine. These data reveal important differences in patterns of brain activation between the drugs. Differences in the involvement in basal ganglia parallel known differences between the drugs in the emergence of acute EPS upon emergency administration.

Adult↗
PubMed2005

Subtle effects of ketamine on memory when administered following stimulus presentation.

RATIONALE: N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., PCP, ketamine) have been shown to impair learning/memory. Well documented in animal models, only limited research in humans has been reported. Findings to date are similar to results of animal studies; however, antagonists are typically administered before the learning experience. This may be problematic as memory failure could be secondary to inattention induced by the psychotomimetic effects of these drugs and/or alterations in sensory processing which can degrade the quality of the stimulus, thereby affecting the accuracy of recall. OBJECTIVE: The objective of the study is to compare the effects of ketamine vs placebo on recall for words when administered after stimulus presentation. METHODS: In this double-blind crossover study, 24 normal controls were given bolus injections of ketamine (0.3 mg/kg) or placebo. Immediately prior to infusion, subjects were administered a verbal memory test. Delayed recall was measured 45 min postinfusion. Mental status changes were assessed using the Brief Psychiatric Rating Scale. RESULTS: Subjects experienced a significant increase in psychiatric symptoms that peaked at 20 min. Results indicate no differences between the drug and placebo conditions for the memory task. However, reminiscence (i.e., recall of previously unrecalled items with repeated testing) was significantly reduced following ketamine administration compared to placebo. CONCLUSIONS: Findings suggest that aspects of memory consolidation are affected by drugs that interfere with NMDA receptor function.

Acoustic Stimulation↗
PubMed2005

Chromatin alterations associated with down-regulated metabolic gene expression in the prefrontal cortex of subjects with schizophrenia.

BACKGROUND: Schizophrenia is frequently accompanied by hypometabolism and altered gene expression in the prefrontal cortex. Cellular metabolism regulates chromatin structure, including covalent histone modifications, which are epigenetic regulators of gene expression. OBJECTIVE: To test the hypothesis that down-regulated metabolic gene expression is associated with histone modification changes in the prefrontal cortex of subjects with schizophrenia. DESIGN AND SUBJECTS: Histones and gene transcripts were profiled in the postmortem prefrontal cortex of 41 subjects with schizophrenia and 41 matched controls. The phosphorylation, acetylation, and methylation of 6 lysine, serine, and arginine residues of histones H3 and H4 were examined together with 16 metabolic gene transcripts using serial immunoblotting, immunohistochemical analysis, custom-made complementary DNA arrays, and quantitative real-time reverse transcriptase-polymerase chain reaction. RESULTS: Subjects with schizophrenia, as a group, showed no significant alterations in histone profiles or gene expression. In a subgroup of 8 patients with schizophrenia, levels of H3-(methyl)arginine 17, H3meR17, exceeded control values by 30%, and this was associated with the decreased expression of 4 metabolic transcripts. CONCLUSIONS: High levels of H3-(methyl)arginine 17 are associated with down-regulated metabolic gene expression in the prefrontal cortex of a subset of subjects with schizophrenia. Histone modifications may contribute to the pathogenesis of prefrontal dysfunction in schizophrenia.

Chromatin↗