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Biomedical subjects

Kenneth L Davis

Publications and source records attributed to Kenneth L Davis.

At least 37 records · Page 2Linked to original sources
PubMed2004

GAD67 and GAD65 mRNA and protein expression in cerebrocortical regions of elderly patients with schizophrenia.

Gamma-Aminobutyric acid (GABA), the principal inhibitory neurotransmitter of CNS, has been consistently implicated in the pathophysiology of schizophrenia. GABA is synthesized from glutamate by the enzyme glutamic acid decarboxylase (GAD). Two isoforms of GAD have been identified and have been named GAD65 and GAD67 based on their apparent molecular weights. In this study, GAD65 and GAD67 mRNA and protein levels were measured by using real-time RT-PCR and immunoblotting, respectively, in post-mortem brain tissue from the dorsolateral prefrontal cortex (DLPFC) and the occipital cortex of the elderly persons with schizophrenia and matched normal controls. In addition, the mRNA expression of GAT-1, one of the principal transporters of GABA, was also studied in the same subjects. Expression of GAD65 and GAD67 mRNA in the DLPFC and in the occipital cortex was significantly elevated in patients with schizophrenia, whereas the expression of the corresponding proteins and GAT-1 mRNA was unchanged. Although the levels of GAD65 and GAD67 messages were increased in schizophrenia subjects, the proportion of the two GAD isoforms remained constant in controls and schizophrenics. In the human DLPFC, GAD65 mRNA was found to be expressed significantly less than the message for GAD67, approximately 16% of that observed for GAD67. On the contrary, the abundance of GAD65 protein in the DLPFC was about 350% of that observed for GAD67. The results suggest a substantial dysregulation of GAD mRNA expression in schizophrenia and, taken together with the results of protein expression studies, raise the possibility that both cortical and subcortical GABA function may be compromised in the disease.

Aged↗
PubMed2004

Expression of the ionotropic glutamate receptor subunits and NMDA receptor-associated intracellular proteins in the substantia nigra in schizophrenia.

Multiple neurotransmitter systems have been implicated in the pathophysiology of schizophrenia. Dopamine hyperactivity has often been implicated in this illness. More recently, the glutamate hypothesis of schizophrenia suggests that NMDA receptor (NMDAR) hypofunction may also play a role in this illness. This is based primarily on studies showing that phencyclidine, an NMDAR antagonist, can induce a schizophreniform psychosis. While NMDAR dysfunction is most often implicated in schizophrenia, other components of the glutamate system, such as the AMPA and kainate receptors, as well as NMDAR-associated intracellular proteins, may also play a role in regulating NMDA receptor activity and glutamate neurotransmission. There is growing interest in the hypothesis that the pathophysiology of schizophrenia involves alterations in dopamine-glutamate interactions. The glutamate system is anatomically and functionally linked to the dopamine system, and glutamate can modulate dopaminergic activity and release by stimulating various glutamate receptor subtypes expressed by dopaminergic neurons in the substantia nigra/ventral tegmental area. In this study, we investigated dopamine-glutamate interactions by measuring the expression of transcripts encoding the subunits for the ionotropic glutamate receptors (NMDA, AMPA and kainate) and five NMDAR-associated intracellular proteins, PSD-93, PSD-95, SAP102, NF-L and yotiao in the dopaminergic neurons in the substantia nigra pars compacta (SNc) of subjects with schizophrenia and a comparison group. Tyrosine hydroxylase (TH, a marker of dopamine-synthesizing cells), NR1 (an NMDA receptor subunit) and GluR5 (a kainate subunit) transcript levels were significantly increased in the SNc in schizophrenia. These data support the hypothesis that schizophrenia may involve alterations in dopamine-glutamate interactions.

A Kinase Anchor Proteins↗
PubMed2004

Working memory performance in poor outcome schizophrenia: relationship to age and executive functioning.

Performance on the Letter-Number Sequencing (LNS) and Wisconsin Card Sorting Tests (WCST) have been shown to be significantly correlated in patients with schizophrenia, a relationship postulated to be due to working memory demands of the two tests (Gold, Carpenter, Randolph, Goldberg, & Weinberger, 1997). An alternative explanation for the association between these two tests is their sorting demands, in that both require sorting of information albeit in slightly different ways. If the latter explanation is valid, then working memory tasks that do not require sorting or other conceptualization demands should be less predictive of WCST performance than LNS. These hypotheses were examined in 34 poor outcome patients with schizophrenia, one-half of whom were over the age of 65. Patients were evaluated on Digit Span Forward, spatial working memory, LNS, and the WCST. It was found that WCST performance was significantly associated with performance on the LNS but no other working memory task. Age related performance differences were greatest on the WCST Categories and floor effects were noted on this test in one-half of the subjects. Analyses predicting WCST Categories in subjects whose scores were greater than zero (n = 16) also demonstrated that LNS, but not Digit Span or spatial working memory (any delay) predicted WCST performance. These findings indicate that LNS may be an index of executive functioning, particularly in patients who cannot perform the WCST.

Adult↗
PubMed2004

The pathophysiology of schizophrenia disorders: perspectives from the spectrum.

OBJECTIVE: This overview focuses on neurobiological abnormalities found in subjects with schizotypal personality disorder, the prototype of the schizophrenia spectrum disorders, and chronic schizophrenia in the context of common vulnerabilities shared by schizotypal personality disorder and schizophrenia, as well as the factors that protect against the severe cognitive/social deficits and frank psychosis of chronic schizophrenia. A pathophysiological model of the relationship between schizotypal personality disorder and schizophrenia was developed based on this data. METHOD: The authors provide a selective review of major findings regarding the pathophysiology of schizotypal personality disorder and integrate these results in conjunction with preclinical studies into a model of the pathophysiology of the spectrum. RESULTS: People with schizotypal personality disorder share phenomenological, genetic, and cognitive abnormalities with people with chronic schizophrenia. While temporal volume reductions appear to be common to both groups, there may be preservation of frontal lobe volume in schizotypal personality disorder compared to schizophrenia. Findings to date regarding striatal volume, metabolic rate, and dopamine release in subjects with schizotypal personality disorder compared to subjects with chronic schizophrenia are consistent with hypotheses of reduced striatal dopaminergic activity in schizotypal personality disorder compared to schizophrenia. CONCLUSIONS: Genetic or environmental factors that promote greater frontal capacity and reduced striatal dopaminergic reactivity might contribute to sparing people with schizotypal personality disorder from the psychosis and severe social and cognitive deterioration of chronic schizophrenia. Further research is required to test these hypotheses more definitively.

Atrophy↗
PubMed2004

Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism.

OBJECTIVE: Autism/autistic disorder (MIM number 209850) is a complex, largely genetic psychiatric disorder. The authors recently mapped a susceptibility locus for autism to chromosome region 2q24-q33 (MIM number 606053). In the present study, genes across the 2q24-q33 interval were analyzed to identify an autism susceptibility gene in this region. METHOD: Mutation screening of positional candidate genes was performed in two stages. The first stage involved identifying, in unrelated subjects showing linkage to 2q24-q33, genetic variants in exons and flanking sequence within candidate genes and comparing the frequency of the variants between autistic and unrelated nonautistic subjects. Two single nucleotide polymorphisms (SNPs) that showed evidence for divergent distribution between autistic and nonautistic subjects were identified, both within SLC25A12, a gene encoding the mitochondrial aspartate/glutamate carrier (AGC1). In the second stage, the two SNPs in SLC25A12 were further genotyped in 411 autistic families, and linkage and association tests were carried out in the 197 informative families. RESULTS: Linkage and association were observed between autistic disorder and the two SNPs, rs2056202 and rs2292813, found in SLC25A12. Using either a single affected subject per family or all affected subjects, evidence for excess transmission was found by the Transmission Disequilibrium Test for rs2056202, rs2292813, and a two-locus G*G haplotype. Similar results were observed using TRANSMIT for the analyses. Evidence for linkage was supported by linkage analysis with the two SNPs, with a maximal multipoint nonparametric linkage score of 1.57 and a maximal multipoint heterogeneity lod score of 2.11. Genotype relative risk could be estimated to be between 2.4 and 4.8 for persons homozygous at these loci. CONCLUSIONS: A strong association of autism with SNPs within the SLC25A12 gene was demonstrated. Further studies are needed to confirm this association and to decipher any potential etiological role of AGC1 in autism.

Aspartic Acid↗
PubMed2004

Mitochondrial enzymes in schizophrenia.

The responses of brain metabolism and blood flow to stimulation are diminished in the dorsolateral prefrontal cortexes (DLPFCs) of schizophrenic patients. Reductions in mitochondrial enzymes underlie diminished metabolism in several neurodegenerative diseases. Thus, we tested whether reductions in selected mitochondrial enzymes could underlie the changes in schizophrenia. The activities of the pyruvate dehydrogenase complex (PDHC), aconitase, isocitrate dehydrogenase (ICDH), and the alpha-ketoglutarate dehydrogenase complex (KGDHC) were determined on DLPFCs from patients with schizophrenia (n=26) and normal nonpsychiatric disease controls (n=13). The enzyme activities (mU/mg protein; mean +/- SEM) were similar (values for controls and schizophrenic patients, respectively) for PDHC (11.36 +/-1.5, 10.33 +/- 0.8), aconitase (1.06 +/- 0.1, 1.35 +/- 0.2), ICDH (31.70 +/- 2.7, 32.00 +/- 2.6), and KGDHC (2.62 +/- 0.4, 3.09 +/- 0.3). Separate analyses of the patients matched for age or postmortem interval gave similar conclusions. Cognitive dementia rating scores correlated poorly with activities of PDHC, aconitase, ICDH, and KGDHC. In one schizophrenic patient, activity of aconitase was undetectable, and in two others KGDHC activity was very low. Both had low activities of ICDH. A reduced activity of these enzymes in a subgroup is consistent with other data, suggesting that some patients with schizophrenia have abnormalities in brain mitochondria. However, in schizophrenia, unlike a number of neurodegenerative diseases, reductions in the activities of the key mitochondrial enzymes KGDHC and PDHC are not frequent.

Aconitate Hydratase↗
PubMed2003

Dementia rating and nicotinic receptor expression in the prefrontal cortex in schizophrenia.

BACKGROUND: The etiology of dementia that occurs in patients with schizophrenia is not well understood. Nicotinic acetylcholine receptors have been implicated in cognitive function, and deficits in these receptors have been reported in schizophrenia. METHODS: The present study investigates possible associations of nicotinic receptor subunit expression in the dorsal lateral prefrontal cortex, an area known to be affected in schizophrenia, and dementia rating. RESULTS: alpha7 immunoreactivity was reduced by 20% to 28% and [(3)H]epibatidine binding was increased twofold in groups of patients with schizophrenia compared to normal control subjects matched for age, postmortem delay, and low levels of brain nicotine and cotinine. In contrast, no significant differences in alpha4, alpha3, or beta2 immunoreactivity or alpha7 messenger RNA expression were observed in schizophrenia patients compared with control subject values. Clinical dementia ratings in patients with schizophrenia were correlated with neither [(3)H]epibatidine binding nor nicotinic receptor subunit expression. CONCLUSIONS: These data indicate no relationship between the trend for reduced neocortical alpha7 subunit protein expression in schizophrenia and dementia. Further investigations are required to establish whether the reduction in alpha7 protein in the dorsal lateral prefrontal cortex is associated with clinical features other than dementia in schizophrenia.

Aged↗
PubMed2003

Novel putative nonprotein-coding RNA gene from 11q14 displays decreased expression in brains of patients with schizophrenia.

A modified method of differential display was employed to identify a novel gene (named PSZA11q14), the expression of which was reduced in brains from patients with schizophrenia. Decreased expression of PSZA11q14 was identified initially in Brodmann's area (BA) 21 from a small group of patients with schizophrenia (n = 4) and normal controls (n = 6) and was confirmed subsequently using independent RT-PCR assay in BA 21, 22, and 9, and in hippocampus from a larger group of patients with schizophrenia (n = 36) and controls (n = 35). PSZA11q14 is located on chromosome 11q14, an area shown previously to co-segregate with schizophrenia and related disorders in several families. Decreased expression of PSZA11q14 in patients with schizophrenia and its location on 11q14 provide converging lines of evidence indicating that PSZA11q14 may be involved in at least some cases of schizophrenia. PSZA11q14 shows no significant homology with any known gene. It has no introns and produces two RNA transcripts of approximately 4.5 and approximately 7.0 kb. The largest open reading frame (ORF) in the PSZA11q14 transcripts may potentially encode for a short polypeptide of 71 amino acids. High frequency of rare codons, the short size of this ORF, and low homology with mouse sequences, however, indicate that PSZA11q14 may instead represent a novel member of a family of nonprotein-coding RNA genes that are not translated and that function at the RNA level. PSZA11q14 is located within the first intron of the DLG-2 gene and transcribed in the opposite direction to DLG-2. These results suggest that PSZA11q14 may be considered a candidate gene for schizophrenia acting as an antisense regulator of DLG-2, which controls assembling functional N-methyl-D-aspartate (NMDA) receptors.

Adolescent↗
PubMed2003

Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia.

BACKGROUND: Brain imaging, molecular genetic, and ultrastructural evidence indicate the existence of pathologic alterations in the cortical and subcortical white matter of schizophrenic patients. METHODS: We performed a stereologic analysis of numbers, densities, and spatial distribution of oligodendrocytes in layer III and in the gyral white matter of Brodmann's area 9 in the superior frontal gyrus to assess whether these cells are affected in schizophrenia. Counts were obtained on Nissl-stained materials and on sections immunolabeled for the oligodendrocyte marker 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) in seven schizophrenic and seven age-matched control cases. RESULTS: A 28% decrease in total numbers (or densities) of cortical layer III oligodendrocytes and a 27% decrease in the white matter were detected in schizophrenic compared with control cases based on CNPase immunostaining. Nissl and CNPase immunohistochemistry yielded comparable results. The spatial distribution of oligodendrocytes in area 9 white matter exhibited a less clustered arrangement in schizophrenic cases. CONCLUSIONS: These results suggest a severe pathology of oligodendrocytes in schizophrenia and provide a quantitative cellular correlate of the white matter changes observed by brain imaging in vivo, showing reduced fractional anisotropy in schizophrenia. The data support recent evidence that several genes encoding myelin-related proteins consistently exhibit reduced expression in schizophrenia.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2003

Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial.

CONTEXT: Laboratory evidence that inflammatory mechanisms contribute to neuronal injury in Alzheimer disease (AD), along with epidemiological evidence, suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) may favorably influence the course of the disease. OBJECTIVE: To determine whether treatment with a selective cyclooxygenase (COX) -2 inhibitor (rofecoxib) or a traditional nonselective NSAID (naproxen) slows cognitive decline in patients with mild-to-moderate AD. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to study medications. SETTING: Forty ambulatory treatment centers affiliated with the Alzheimer's Disease Cooperative Study consortium. PARTICIPANTS: Participants with mild-to-moderate AD (Mini-Mental State Examination score of 13-26) were recruited from December 1999 to November 2000 using clinic populations, referrals from community physicians, and local advertising. Stable use of cholinesterase inhibitors, estrogen, low-dose aspirin, and vitamin E was allowed. Participants with inflammatory diseases that might respond to the study medications were excluded. Of 474 participants screened, 351 were enrolled. INTERVENTIONS: Once-daily rofecoxib, 25 mg, or twice-daily naproxen sodium, 220 mg, or placebo. MAIN OUTCOME MEASURES: The primary outcome measure was the 1-year change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score. Secondary outcome measures included the Clinical Dementia Rating scale sum-of-boxes, the Neuropsychiatric Inventory, the Quality of Life-AD, and the time to attainment of significant end points (4-point decline from baseline ADAS-Cog score, 1-step worsening on the global Clinical Dementia Rating scale, 15-point decline on the ADCS activities of daily living inventory, institutionalization, or death). RESULTS: The 1-year mean (SD) change in ADAS-Cog scores in participants treated with naproxen (5.8 [8.0]) or rofecoxib (7.6 [7.7]) was not significantly different from the change in participants treated with placebo (5.7 [8.2]). Results of secondary analyses showed no consistent benefit of either treatment. Fatigue, dizziness, and hypertension were more commonly reported in the active drug groups, and more serious adverse events were found in the active treatment group than in the placebo group. CONCLUSION: The results of this study indicate that rofecoxib or low-dose naproxen does not slow cognitive decline in patients with mild-to-moderate AD.

Activities of Daily Living↗
PubMed2003

White matter changes in schizophrenia: evidence for myelin-related dysfunction.

Numerous lines of inquiry implicate connectivity as a central abnormality in schizophrenia. Myelination and factors that affect myelination, such as the function of oligodendroglia, are critical processes that could profoundly affect neuronal connectivity, especially given the diffuse distribution of oligodendrocytes and the widespread distribution of brain regions that have been implicated in schizophrenia. Multiple lines of evidence now converge to implicate oligodendroglia and myelin in schizophrenia. Imaging and neurocytochemical evidence, similarities with demyelinating diseases, age-related changes in white matter, myelin-related gene abnormalities, and morphologic abnormalities in the oligodendroglia demonstrated in schizophrenic brains are all examined in light of the hypothesis that oligodendroglial dysfunction and even death, with subsequent abnormalities in myelin maintenance and repair, contribute to the schizophrenic syndrome.

Age Factors↗
PubMed2003

Lack of association between the levels of the low-density lipoprotein receptor-related protein (LRP) and either Alzheimer dementia or LRP exon 3 genotype.

The low-density lipoprotein receptor-related protein (LRP), which interacts with the Alzheimer disease (AD) beta-amyloid precursor protein (APP), represents an important pathway in AD pathology. LRP-mediated receptor pathways appear to regulate both the production and the clearance of amyloid beta-protein (Abeta), a principal neuropathological product in AD. Several conflicting studies have examined levels of LRP in AD brains, as well as the relationship between the LRP exon 3 (C766T) polymorphism and LRP levels and/or disease susceptibility. In order to further investigate the role of LRP in AD, we examined well-characterized brain samples collected from subjects with varying degrees of cognitive impairment for LRP protein expression levels as well as for the presence of the LRP exon 3 polymorphism. We found no correlation between LRP levels and either presence of the disease or cognitive decline. In addition, we found no correlation between the LRP exon 3 polymorphism and either AD or LRP levels.

Alzheimer Disease↗
PubMed2003

Altered transcript expression of NMDA receptor-associated postsynaptic proteins in the thalamus of subjects with schizophrenia.

OBJECTIVE: NMDA receptor dysfunction has been implicated in the pathophysiology of schizophrenia. The NMDA receptor is a multimeric ligand-gated ion channel, and the obligate NR(1) subunit is expressed as one of eight isoforms due to the alternative splicing of exons 5, 21, and 22. Alternative splicing of NR(1) subunits modulates receptor function by influencing the association of NR(1) with other NMDA receptor subunits and myriad intracellular molecules, such as the postsynaptic density family of proteins that target NMDA receptors to the synaptic membrane and couple it to numerous signal transduction enzymes. Recently, the authors reported that the NMDA receptor subunits NR(1) and NR(2C) are abnormally expressed in the thalamus in schizophrenia. They hypothesized that this reduction is associated with specific NR(1) isoforms and that NMDA receptor-related postsynaptic density proteins are abnormally expressed. METHOD: Using in situ hybridization, the authors examined expression of the transcripts encoding NR(1) isoforms containing exons 5, 21, or 22, and the NMDA receptor-related postsynaptic density proteins NF-L, PSD93, PSD95, and SAP102. RESULTS: Reduced NR(1) subunit transcript expression was restricted to exon 22-containing isoforms. Increased expression of the NMDA receptor-associated postsynaptic density proteins NF-L, PSD95, and SAP102 was also detected in the thalamus of subjects with schizophrenia. CONCLUSIONS: These data support the hypothesis of glutamatergic abnormalities in schizophrenia and suggest that glutamatergic dysfunction may occur not only at the level of receptor expression but also within intracellular pathways associated with glutamate receptor-associated signal transduction.

Aged↗
PubMed2002

Developing novel treatments for mood disorders: accelerating discovery.

This review was generated from discussions by the Pharmacologic and Somatic Treatments Section of the National Institute of Mental Health Strategic Plan for Mood Disorders Committee on advancing novel pharmacologic and somatic treatments for mood disorders. The opening section of the article summarizes in broad strokes, current pharmacologic treatments, and new directions in the field. Thereafter the topics focus on specific research initiatives that could advance the current therapeutics for mood disorders including new basic and clinical research in vivo human imaging procedures, somatic therapeutics, and the vast new area of pharmacogenetics. New scientific and technical opportunities exist today based on advances in basic neuroscience, opportunities in clinical testing, industry interest in advancing central nervous system therapeutics, and on active consumer advocacy groups. The question of how to bring all of these positive forces together to accelerate discovery in mood disorder thera-peutics is the topic of this article.

Animals↗
PubMed2002

Kraepelinian and non-Kraepelinian schizophrenia subgroup differences in cerebral metabolic rate.

We studied two subtypes of schizophrenia. the Kraepelinian subtype (n = 10) characterized by an unremitting and severe course and the non-Kraepelinian subtype (n = 17) characterized by a remitting course and some periods of self-care. Patients were assessed with positron emission tomography (PET) with 18F-deoxyglucose (FDG) and high-resolution magnetic resonance imaging (MRI). A group of 32 age- and sex-matched normal volunteers served as comparison subjects. During the FDG tracer uptake period, patients performed a serial verbal learning task. MR images were segmented into gray, white and cerebrospinal fluid regions, and warped to average normal coordinates. PET images were coregistered to the MR images and similarly warpedfor analysis. Kraepelinian subtype patients were characterized by lower metabolic rates in the temporal lobe and cingulategyrus. and lower fronto/occipital ratios than non-Kraepelinian subtype patients. Exploratory statistical probability mapping alsorevealed lower metabolic rates in the right striatum in Kraepelinian versus non-Kraepelinian patients. These differences couldnot be attributed to differences in age, symptom severity, task performance during FDG uptake, or severity of involuntary movements. Factor analysis of the cortical surface identified significantly lower temporal lobe metabolic rates in Kraepelinian patients than non-Kraepelinian patients. A combined frontal/temporal deficit or greater cortical change may be associated with poorer longitudinal course.

Activities of Daily Living↗