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Kenneth L Davis

Publications and source records attributed to Kenneth L Davis.

At least 19 recordsLinked to original sources
PubMed2007

Expression of transcripts for myelination-related genes in the anterior cingulate cortex in schizophrenia.

Several recent studies have found changes in the expression of genes functionally related to myelination and oligodendrocyte homeostasis in schizophrenia. These studies utilized microarrays and quantitative PCR (QPCR), methodologies which do not permit direct, unamplified examination of mRNA expression. In addition, these studies generally only examined transcript expression in homogenates of gray matter. In the present study, we examined the expression of myelination-related genes previously implicated in schizophrenia by microarray or QPCR. Using in situ hybridization, we measured transcript expression of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), myelin-associated glycoprotein (MAG), transferrin (TF), quaking (QKI), gelsolin, myelin oligodendrocyte glycoprotein, v-erb-b2 erythroblastic leukemia viral oncogene homolog 3, erbb2 interacting protein, motility-related protein-1, SRY-box containing gene 10, oligodendrocyte transcription factor 2, peripheral myelin protein 22, and claudin-11 in both gray and white matter of the anterior cingulate cortex (ACC) in subjects with schizophrenia (n=41) and a comparison group (n=34). We found decreased expression of MAG, QKI, TF, and CNP transcripts in white matter. We did not find any differences in expression of these transcripts between medicated (n=31) and unmedicated (n=10) schizophrenics, suggesting that these changes are not secondary to treatment with antipsychotics. Finally, we found significant positive correlations between QKI and MAG or CNP mRNA expression, suggesting that the transcription factor QKI regulates MAG and CNP expression. Our results support the hypothesis that myelination and oligodendrocyte function are impaired in schizophrenia.

Aged↗
PubMed2006

Long-term outcomes in chronically hospitalized geriatric patients with schizophrenia: retrospective comparison of first generation and second generation antipsychotics.

INTRODUCTION: Some groups have reported the longitudinal course of elderly poor outcome schizophrenic patients to be characterized by progressive decline in cognitive functions and functional capacity. Although many of these patients experience minimal reduction of psychotic symptoms, there may be beneficial effects of antipsychotic treatments on cognitive functions and functional capacity. METHODS: This naturalistic study compared the longitudinal course of psychotic symptoms, cognitive functions and functional impairment in geriatric schizophrenic patients treated with first generation (N=97) or second generation (N=78) antipsychotic medications. Mixed effects linear regression analyses were used to examine the effects of treatment (first generation vs. second generation antipsychotic), time and treatment x time. RESULTS: Cognitive functions (Mini Mental State Examination time effect estimate=-.41, p<.001; ADAS-L Cog time effect estimate=.64, p<.001) and self-care skills (ADAS-L Self-Care time effect estimate=.65, p<.001) declined over time for the subject group as a whole and this decline was not modified by treatment with second generation antipsychotics relative to first generation antipsychotics. Similarly, second generation antipsychotic treatment produced no effect on the progressive worsening of negative symptom over time. CONCLUSION: This long-term naturalistic study of poor outcome geriatric patients with schizophrenia did not find atypical antipsychotics to produce any differential protective effect relative to typical antipsychotics on the long-term manifestations of symptoms, cognition and self-care in poor outcome geriatric schizophrenic patients.

Aged↗
PubMed2006

Diffusion tensor imaging in schizophrenia.

BACKGROUND: Alignment of white matter axons as inferred from diffusion tensor imaging has indicated changes in schizophrenia in frontal and frontotemporal white matter. METHODS: Diffusion tensor anisotropy and anatomical magnetic resonance images were acquired in 64 patients with schizophrenia and 55 normal volunteers. Anatomical images were acquired with a magnetization prepared rapid gradient echo sequence, and diffusion tensor images used a pulsed gradient spin-echo acquisition. Images were aligned and warped to a standard brain, and anisotropy in normal volunteers and patients was compared using significance probability mapping. RESULTS: Patients showed widespread areas of reduced anisotropy, including the frontal white matter, the corpus callosum, and the frontal longitudinal fasciculus. CONCLUSIONS: These findings, which are consistent with earlier reports of frontal decreases in anisotropy, demonstrate that the effects are most prominent in frontal and callosal areas and are particularly widespread in frontal white matter regions.

Adolescent↗
PubMed2006

Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia.

Abnormal oligodendrocyte function has been postulated as a primary etiological event in schizophrenia. Oligodendrocyte lineage transcription factor 2 (OLIG2) encodes a transcription factor central to oligodendrocyte development. Analysis of OLIG2 in a case-control sample (n = approximately 1,400) in the U.K. revealed several SNPs to be associated with schizophrenia (minimum P = 0.0001, gene-wide P = 0.0009). To obtain independent support for this association, we sought evidence for genetic interaction between OLIG2 and three genes of relevance to oligodendrocyte function for which we have reported evidence for association with schizophrenia: CNP, NRG1, and ERBB4. We found interaction effects on disease risk between OLIG2 and CNP (minimum P = 0.0001, corrected P = 0.008) for interaction with ERBB4 (minimum P = 0.002, corrected P = 0.04) but no evidence for interaction with NRG1. To investigate the biological plausibility of the interactions, we sought correlations between the expression of the genes. The results were similar to those of the genetic interaction analysis. OLIG2 expression significantly correlated in cerebral cortex with CNP (P < 10(-7)) and ERBB4 (P = 0.002, corrected P = 0.038) but not NRG1. In mouse striatum, Olig2 and Cnp expression also was correlated, and linkage analysis for trans-effects on gene expression suggests that each locus regulates the other's expression. Our data provide strong convergent evidence that variation in OLIG2 confers susceptibility to schizophrenia alone and as part of a network of genes implicated in oligodendrocyte function.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2006

82-kDa choline acetyltransferase is in nuclei of cholinergic neurons in human CNS and altered in aging and Alzheimer disease.

Cholinergic neurons express choline acetyltransferase (ChAT) which synthesizes acetylcholine. We show here for the first time that primate-specific 82-kDa ChAT is expressed in nuclei of cholinergic neurons in human brain and spinal cord; isoform-specific antibodies were used to compare localization patterns and temporal expression of the more abundant 69-kDa ChAT and primate-specific 82-kDa ChAT in necropsy tissues. The 82-kDa ChAT co-localizes with 69-kDa ChAT in well-characterized cholinergic areas, but is also found in the claustrum which does not contain 69-kDa ChAT. Cholinergic neuron function changes with increasing age and are targeted in neurodegenerative diseases such as AD, thus we compared expression and subcellular localization of 69- and 82-kDa ChAT in necropsy brain samples from control subjects of varying ages and from Alzheimer disease (AD) subjects. The 82-kDa ChAT protein was expressed in cholinergic neurons in brain from birth until the eighth decade of life and in AD, but the subcellular staining pattern and proportion of neurons that were immunopositive changed with increasing age and in AD.

Adolescent↗
PubMed2006

Seasonality effects on schizophrenic births in multiplex families in a tropical island.

Many studies have found that individuals with schizophrenia have been born in winter months in disproportionately high numbers. Temperature and weather effects, such as hot summers or cold winters, have been among the suggested explanations for this seasonality effect. We studied the relationship between schizophrenia and season of birth in Puerto Rico, a tropical island with mild seasonal variation of temperature and virtually no cold periods. Our sample consisted of 132 subjects (57 with schizophrenia, 75 without) from 24 multiplex families. Schizophrenic family members were significantly more likely to be born during the winter months (21/57; 36.8%) than their unaffected relatives (16/75; 21.3%). These results suggest that extreme temperatures are not a sufficient explanation for the seasonality effect and that other factors associated with seasonality may have an effect on the later development of schizophrenia. The fact that a seasonality effect was found in a group likely to have an increased genetic loading for schizophrenia suggests that seasonality may be associated with a second, environmental "hit" in a "two-hit hypothesis" of schizophrenia.

Adult↗
PubMed2006

Validity and stability of performance-based estimates of premorbid educational functioning in older patients with schizophrenia.

This paper presents the results of two studies of the validity of word-recognition reading as an indicator of premorbid functioning in schizophrenia. The first examined the stability over a 6-year follow-up period of word recognition reading compared to other aspects of cognitive functioning, including verbal learning and delayed recall, verbal fluency, constructional skills, and naming ability. The second study examined the relative predictive power of indicators of premorbid functioning as compared to current cognitive functioning for the prediction of current social and self-care skills. In the first study 218 patients with chronic schizophrenia participated. For the second study, 231 male veterans with schizophrenia were assessed for cognitive functioning, indicators of premorbid adjustment, and current functional status. Analyses of the differences between correlations indicated that word recognition reading ability was significantly more stable than other aspects of cognitive functioning over a six-year period during which decline in some other aspects of performance was found. In the second study, premorbid educational and social attainment, word recognition reading skill, and current cognitive functioning were all significantly related to current functional status, defined by correlations with ratings of current functional status. Path analyses indicated, however, that current cognitive functioning was the only significant predictor of current functional status when the intercorrelations of the variables were considered. In sum, Premorbid functioning estimated with word-recognition reading was stable over time (study 1) and correlated with both current cognitive and functional status (study 2). The results of these two studies suggest that word-recognition reading skills are useful screening instruments to estimate premorbid functioning even in deteriorated patients with schizophrenia.

Achievement↗
PubMed2006

The human homolog of the QKI gene affected in the severe dysmyelination "quaking" mouse phenotype: downregulated in multiple brain regions in schizophrenia.

OBJECTIVE: The authors sought to understand the origins of oligodendrocyte/myelin gene expression abnormalities in the brains of persons with schizophrenia. METHOD: Twelve cortical regions (Brodmann's areas 8, 10, 44, 46, 23/31, 24/32, 20, 21, 22, 36/28, 7, and 17) and three noncortical regions (caudate, hippocampus, and putamen) of 16 elderly schizophrenia patients and 14 matched comparison subjects were examined using 450 separate microarrays. The mRNA levels of QKI and its isoforms were then measured in a larger cohort by using quantitative real-time polymerase chain reaction (qPCR) in the cingulate cortex of schizophrenia subjects and matched comparison subjects. RESULTS: Expression of QKI mRNA was decreased in seven cortical regions and the hippocampus in the schizophrenia subjects. QKI gene expression deficits detected by microarray were validated by qPCR in the cingulate cortex, where the expression of isoforms QKI-5, QKI-6, and QKI-7 were profoundly perturbed in schizophrenia. CONCLUSIONS: Since QKI plays a fundamental role in oligodendrocyte differentiation and in myelination, its underexpression may be pivotal to, and upstream of, other myelin-associated gene expression abnormalities in schizophrenia. Given the role of QKI in determination of oligodendrocyte fate, these results not only confirm oligodendrocyte-related gene expression abnormalities in schizophrenia but suggest that the physiology of glial progenitor cells may be altered in schizophrenia.

Aged↗
PubMed2005

Myelin-associated mRNA and protein expression deficits in the anterior cingulate cortex and hippocampus in elderly schizophrenia patients.

Microarray and other studies have reported oligodendrocyte and myelin-related (OMR) deficits in schizophrenia. Here, we employed a quantitative approach to determine the magnitude of OMR gene expression deficits and their brain-region specificity. In addition, we examined how expression levels among the studied OMR genes are interrelated. mRNA of MAG, CNP, SOX10, CLDN11, and PMP22, but not MBP and MOBP, was reduced in the hippocampus and anterior cingulate cortex but not in the putamen of patients with schizophrenia. Expression of the only protein examined (CNP) was decreased in the hippocampus but not in the putamen. Correlation and factor analyses revealed that mRNA levels for genes that did exhibit differential expression in schizophrenia (MAG, CNP, SOX10, CLDN11, and PMP2), as opposed to those that did not (MOBP and MBP), loaded on separate factors. Thus, OMR gene and protein expression deficits in schizophrenia are brain-region specific, and the affected components may share regulatory elements.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗
PubMed2005

Metabotropic glutamate receptor protein expression in the prefrontal cortex and striatum in schizophrenia.

We investigated the expression of metabotropic glutamate receptors (mGluR) in the prefrontal cortex (PFC) and striatum in schizophrenia. mGluRs modulate the release and reuptake of synaptic glutamate and mediate some molecular correlates of neuroplasticity, including long-term potentiation. The mGluRs are expressed widely in the PFC and striatum, regions often implicated in the pathophysiology of schizophrenia. Thus, we hypothesized that abnormal expression of mGluRs might contribute to glutamatergic dysfunction observed in the PFC and striatum in schizophrenia. Accordingly, we measured the expression of metabotropic glutamate receptors (mGluRs) in Brodmann areas 9, 11, 32, and 46 in the prefrontal cortex (PFC) and the caudate, putamen, and nucleus accumbens in schizophrenia (16 cases, 9 controls) by Western blot analysis. We found an increase in the expression of mGluR1a and mGluR2/3 immunoreactivity in the PFC in schizophrenia, while no changes in the expression of mGluR4a or mGluR5 were detected in this region. In the striatum we found no changes in the expression of any of the mGluRs studied. These results suggest that alterations of mGluR1a and mGluR2/3 expression in the PFC may contribute to the pathophysiology of schizophrenia, and support targeting these receptors for the generation of novel treatment modalities for this disabling illness.

Aged↗
PubMed2005

Variations in myelin and oligodendrocyte-related gene expression across multiple brain regions in schizophrenia: a gene ontology study.

Large-scale gene expression studies in schizophrenia (SZ) have generally focused on the dorsolateral prefrontal cortex. Studies of other brain regions have been less frequent and have rarely been performed in the same subjects. We analyzed postmortem gene expression in multiple cortical regions (Brodmann areas 8, 10, 44, 46, 23/31, 24/32, 20, 21, 22, 36/28, 7 and 17, respectively) as well as in the hippocampus, caudate nucleus, and putamen of 13 SZ and 13 control subjects using Affymetrix GeneChip(R) microarrays. The superior temporal cortex (BA22) and cingulate cortices (BA24/32, 23/31) of subjects with SZ demonstrated more profound alterations of gene expression than other brain regions compared to controls [Katsel, P., Davis, K.L., Gorman, J.M., Haroutunian, V., in press. Variations in differential gene expression patterns across multiple brain regions in schizophrenia. Schizophr. Res.]. Functional categorization of genes whose expression was altered revealed multiple gene ontology classes that included oligodendrocyte/myelin-related genes. These myelin-related ontologies were among the top scored categories in temporal and cingulate gyri and in the hippocampus relative to other brain regions. The most altered transcripts in SZ were those encoding for proteins involved in determination of glial differentiation, myelin structure and adhesion proteins participating in axoglial contacts. Hierarchical clustering demonstrated that these myelin-related gene expression abnormalities in SZ were most pronounced in the hippocampus, superior temporal and cingulate cortices. The high representation of abnormally expressed oligodendrocyte/myelin genes in brain regions with the largest numbers of abnormally expressed genes in SZ confirmed their involvement in the disease process and suggested that the integrity of axon-myelin interaction may be impaired in SZ.

Aged↗
PubMed2005

Increased expression of glutaminase and glutamine synthetase mRNA in the thalamus in schizophrenia.

Numerous molecules enable the handling of glutamate that is destined for neurotransmitter release, including transporters, receptors and glutamatergic enzymes. Previous work in our lab has shown altered levels of transcript expression of excitatory amino acid transporters and a vesicular glutamate transporter in the thalamus in schizophrenia. These changes suggest that molecules that facilitate the release and reuptake of glutamate may be abnormal in schizophrenia. In this study we determined the levels of expression of phosphate activated glutaminase (PAG), which converts glutamine to glutamate, and glutamine synthetase (GS), which converts glutamate to glutamine, with the hypothesis that thalamic PAG and GS transcript expression is altered in schizophrenia. We investigated expression of PAG and GS mRNA using in situ hybridization in six different thalamic nuclei (anterior, dorsomedial, centromedial, ventral anterior, ventral and reticular) from 13 persons with schizophrenia and 8 comparison subjects and found that transcripts for PAG and GS were significantly increased in schizophrenia. Increased PAG and GS transcripts suggest enhanced glutamatergic neurotransmission in the thalamus and its efferent targets in schizophrenia.

Aged↗
PubMed2005

Type 2 diabetes is negatively associated with Alzheimer's disease neuropathology.

BACKGROUND: In cross-sectional and longitudinal studies, type 2 diabetes has been positively associated with the risk of Alzheimer's disease (AD). The present descriptive study compared diabetic and nondiabetic subjects on the severity of neuritic plaques and neurofibrillary tangles (NFTs) in the cerebral cortex and in the hippocampus. METHODS: The study included specimens from 385 consecutive autopsies of residents of a nursing home (15.8% diabetics). Mean age at death = 84 years [standard deviation (SD) = 10], 66% were female, Clinical Dementia Rating mean = 3.0 (SD = 1.6), and 32.5% had an APOE4 allele. Additional analyses limited the sample to 268 subjects (14.1% diabetics) without neuropathology other than AD. RESULTS: Analyses of covariance controlling for age at death, dementia severity (Clinical Dementia Rating score), and APOE4 allele indicated that diabetics had significantly fewer neuritic plaques (p =.008) and NFTs (p =.047) in the cerebral cortex than did nondiabetics. In the hippocampus, diabetics had significantly lower plaque ratings than did nondiabetics (p =.019), but the lower ratings of NFTs did not achieve statistical significance (p =.082). In the entire sample, diabetics had significantly less AD-associated neuropathology in all four analyses. CONCLUSIONS: These results raise the possibility that the varied associations observed between diabetes and AD may be specific to as yet ill-defined subgroups of dementia and diabetic patients or may be more characteristic of younger patients than of those who survive to a mean age of 84 years. Future studies are encouraged to examine a variety of other characteristics such as age that may interact with diabetes affecting the incidence of AD.

Aged↗
PubMed2005

The effect of citalopram adjunctive treatment added to atypical antipsychotic medications for cognitive performance in patients with schizophrenia.

Cognitive enhancement in patients with schizophrenia is a major treatment priority. Because serotonergic approaches have been suggested as a possible mechanism to enhance cognition and many patients with schizophrenia are treated with selective serotonin reuptake inhibitor antidepressants, we evaluated a serotonin reuptake inhibitor, citalopram, as adjunctive therapy to atypical antipsychotic treatment for its cognitive enhancing effects in schizophrenic patients. Nineteen schizophrenic patients were treated in a randomized, placebo-controlled, crossover-designed 24-week study. In phase 1, subjects were randomized equally to 40 mg of citalopram or placebo and were evaluated prior to initiation of pharmacotherapy and at the end of phase 1 (after 12 weeks of treatment with double-blind agent). At the beginning of phase 2, subjects were crossed over to the other treatment and subsequently assessed after 12 weeks of treatment for symptom severity and cognitive performance. There were no statistically significant differences between citalopram 40 mg/d and placebo treatment on any clinical or cognitive measures. These results indicate that citalopram adjunctive treatment to atypical antipsychotics produces no significant cognitive improvement in patients with schizophrenia. Because the subjects in this study were all treated with atypical antipsychotics, it is possible that the pharmacologic profiles of atypical antipsychotic medications at serotonin receptors may have complicated the effects of citalopram augmentation. Further research on alternative serotonergic approaches to cognitive enhancement in schizophrenia is warranted.

Adult↗
PubMed2005

Dopaminergic abnormalities in select thalamic nuclei in schizophrenia: involvement of the intracellular signal integrating proteins calcyon and spinophilin.

OBJECTIVE: While both thalamic abnormalities and dopaminergic dysregulation have been separately implicated in the pathophysiology of schizophrenia, little is known about the possible dysfunction of molecules associated with dopaminergic neurotransmission in the thalamus in this illness. In this study, the authors studied this question by measuring in postmortem brain the expression of molecules associated with dopaminergic neurotransmission. METHOD: Using in situ hybridization and receptor autoradiography, the authors determined in schizophrenia and comparison subjects 1) thalamic expression of the transcripts encoding the five dopamine receptors; 2) binding to the dopamine D(1), D(2), and D(3) receptors; 3) monoaminergic innervation as assessed by binding to the vesicular monoamine transporter; and 4) transcripts encoding three dopamine receptor-associated intracellular proteins (calcyon, spinophilin, and DARPP-32) that mediate integration of dopaminergic signaling with other neurotransmitter systems. RESULTS: Both calcyon and spinophilin transcripts were significantly elevated in schizophrenia subjects. Monoaminergic innervation, as well as dopamine receptor transcripts and binding sites, were unaffected in this illness. CONCLUSIONS: These data indicate that there are dopaminergic abnormalities in the thalamus in schizophrenia but that they are at the level of intracellular integration of dopamine signaling with other neurotransmitter systems, likely including glutamate, in thalamic neurons.

Aged↗