Biomedical subjects

K L Davis

Publications and source records attributed to K L Davis.

At least 19 recordsLinked to original sources

PubMed2001

Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity.

Although there is considerable evidence for a strong genetic component to idiopathic autism, several genomewide screens for susceptibility genes have been performed with limited concordance of linked loci, reflecting either numerous genes of weak effect and/or sample heterogeneity. Because decreasing sample heterogeneity would increase the power to identify genes, the effect on evidence for linkage of restricting a sample of autism-affected relative pairs to those with delayed onset (at age >36 mo) of phrase speech (PSD, for phrase speech delay) was studied. In the second stage of a two-stage genome screen for susceptibility loci involving 95 families with two or more individuals with autism or related disorders, a maximal multipoint heterogeneity LOD score (HLOD) of 1.96 and a maximal multipoint nonparametric linkage (NPL) score of 2.39 was seen on chromosome 2q. Restricting the analysis to the subset of families (n=49) with two or more individuals having a narrow diagnosis of autism and PSD generated a maximal multipoint HLOD score of 2.99 and an NPL score of 3.32. The increased scores in the restricted sample, together with evidence for heterogeneity in the entire sample, indicate that the restricted sample comprises a population that is more genetically homogeneous, which could therefore increase the likelihood of positional cloning of susceptibility loci.

Autistic Disorder↗

PubMed2001

Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia.

Neuropathological and brain imaging studies suggest that schizophrenia may result from neurodevelopmental defects. Cytoarchitectural studies indicate cellular abnormalities suggestive of a disruption in neuronal connectivity in schizophrenia, particularly in the dorsolateral prefrontal cortex. Yet, the molecular mechanisms underlying these findings remain unclear. To identify molecular substrates associated with schizophrenia, DNA microarray analysis was used to assay gene expression levels in postmortem dorsolateral prefrontal cortex of schizophrenic and control patients. Genes determined to have altered expression levels in schizophrenics relative to controls are involved in a number of biological processes, including synaptic plasticity, neuronal development, neurotransmission, and signal transduction. Most notable was the differential expression of myelination-related genes suggesting a disruption in oligodendrocyte function in schizophrenia.

Chronic Disease↗

PubMed2001

Patterns of cortical activity and memory performance in Alzheimer's disease.

BACKGROUND: Declarative memory changes are the hallmark of Alzheimer's disease, although their functional neuroanatomy is not restricted to a single structure. Factor analysis provides statistical methods for evaluating patterns of cerebral changes in regional glucose uptake. METHODS: Thirty-three Alzheimer's patients and 33 age- and gender-matched control subjects were studied with magnetic resonance imaging and positron emission tomography with [(18)F] deoxyglucose. During the tracer-uptake period, subjects performed a serial verbal learning task. Cortical activity was measured in 32 regions of interest, four in each lobe on both hemispheres. RESULTS: Factor analysis with varimax rotation identified seven factors explaining 80% of the variance ("parietal cortex," "occipital cortex," "right temporo-prefrontal areas," "frontal cortex," "motor strip," "left temporal cortex," and "posterior temporal cortex"). Relative to control subjects, Alzheimer's patients showed significantly reduced values on the factors occipital cortex, right temporo-prefrontal areas, frontal cortex, and left temporal cortex. The factor temporo-prefrontal areas showed large differences between patients with good and poor performance, but little difference when control subjects were similarly divided. CONCLUSIONS: Findings suggest that Alzheimer's disease is characterized by altered patterns of cortical activity, rather than deficits in a single location, and emphasize the importance of right temporo-prefrontal circuitry for understanding memory deficits.

Aged↗

PubMed2001

Intraischemic mild hypothermia increases hippocampal CA1 blood flow during forebrain ischemia.

The hippocampal CA1 sector is selectively vulnerable to forebrain ischemia but protected by mild hypothermia. However, the consequence of intraischemic hypothermia on CA1 blood flow during the insult has not been adequately characterized. The effects of mild intraischemic hypothermia on relative changes in regional hippocampal CA1 blood flow were recorded continuously using laser Doppler flowmetry (LDF) during and 30 min after 6 min of forebrain ischemia. Six experimental groups (n=6/group) of fasted male Wistar rats were compared. Groups 1, 3 and 5 consisted of normothermic rats that underwent either 6 (for CBF measurements) and 6 or 10 (for 7 day survival-CA1 neuronal death measurements) min of transient forebrain ischemia using bilateral carotid clamping and hemorrhagic hypotension. Groups 2, 4 and 6 rats were subjected to mild hypothermia (34 degrees C) before, during, and 30 min after 6 (for CBF measurements) and 6 or 10 (for 7 day survival-CA1 neuronal death measurements) min of transient forebrain ischemia. CA1 blood flow and electroencephalogram (EEG) were continuously recorded. During the ischemic insult there were intergroup differences in the magnitude of CBF decreases in the CA1 region. In both groups 1 and 2, CBF returned to preischemic values within 1 min of reperfusion but hypothermic rats had more sustained hyperemia. Hypothermic rats had a quicker recovery of EEG activity and less delayed CA1 neuronal death (group 2 versus 4). These data suggest ischemic blood flow to the CA1 sector was altered by intraischemic mild hypothermia which may contribute to the greater benefit of intraischemic hypothermic neuroprotection.

Animals↗

PubMed2001

Abnormal kainate receptor expression in prefrontal cortex in schizophrenia.

Abnormalities of molecules associated with the glutamate synapse have been implicated in the pathophysiology of schizophrenia. Of the many glutamate receptors, those most commonly suggested to be involved in schizophrenia are the ionotropic subtypes, the NMDA, AMPA, and kainate receptors. Both the NMDA and AMPA subtypes have been extensively studied in postmortem brains of individuals with schizophrenia, but relatively little is known about the expression of the kainate subtype of glutamate receptor. In this study, we have determined cortical and striatal kainate receptor expression in brains from persons with schizophrenia and a comparison group, using both in situ hybridization and receptor autoradiography. At the level of subunit mRNA expression, a shift in subunit stoichiometry was evident in multiple regions of the prefrontal cortex, with increased expression of gluR7 mRNA and decreased expression of KA2 mRNA. Decreased kainate receptor binding was also observed in the subjects with schizophrenia, but was restricted to infragranular laminae of the prefrontal cortex. No differences in kainate receptor binding or subunit mRNA levels were found in striatum or occipital cortex, suggesting that these findings may be restricted to association cortex. These data add to the growing literature implicating ionotropic glutamate receptor disturbances in schizophrenia, and indicate that in addition to AMPA and NMDA receptors, the kainate receptors are also abnormally expressed in this illness.

Aged↗

PubMed2001

Gender differences in poor outcome patients with lifelong schizophrenia.

Gender effects have been reported quite consistently in schizophrenia, with male patients having an earlier age of onset, poorer functional outcome, greater negative symptoms and cognitive impairment, and less severe positive symptoms. Because age of onset, cognitive impairments, and negative symptoms are all correlated with poorer functional status, it is not clear if previously reported gender differences in symptoms are just recapturing gender differences in functional outcome. In this study, 205 geriatric patients with lifelong poor-outcome schizophrenia (43% male) were examined for the severity of schizophrenic symptoms, cognitive impairments, and specific deficits in adaptive skills, as well as for demographic differences such as age at first psychiatric admission, premorbid education, and current treatment status. Previously reported gender differences were replicated in these patients with a uniformly poor functional outcome, with male patients having more severe negative symptoms and an earlier age of first psychiatric admission. No differences in cognitive functioning or specific functional deficits were found, however. These findings suggest that negative symptom severity is greater in male patients regardless of functional outcome and that the association of cognitive deficits with gender may be found only in patients with better functional outcome. The study of gender-related differences in brain structure or function and their interaction with overall course of illness might help understand these differences in symptom presentation.

Activities of Daily Living↗

PubMed2001

Novel effects of nitric oxide.

Nitric oxide (NO), a simple free radical gas, elicits a surprisingly wide range of physiological and pathophysiological effects. NO interacts with soluble guanylate cyclase to evoke many of these effects. However, NO can also interact with molecular oxygen and superoxide radicals to produce reactive nitrogen species that can modify a number of macromolecules including proteins, lipids, and nucleic acids. NO can also interact directly with transition metals. Here, we have reviewed the non--3',5'-cyclic-guanosine-monophosphate-mediated effects of NO including modifications of proteins, lipids, and nucleic acids.

Animals↗

PubMed2001

Erythroid cell growth and differentiation in vitro in the simulated microgravity environment of the NASA rotating wall vessel bioreactor.

Prolonged exposure of humans and experimental animals to the altered gravitational conditions of space flight has adverse effects on the lymphoid and erythroid hematopoietic systems. Although some information is available regarding the cellular and molecular changes in lymphocytes exposed to microgravity, little is known about the erythroid cellular changes that may underlie the reduction in erythropoiesis and resultant anemia. We now report a reduction in erythroid growth and a profound inhibition of erythropoietin (Epo)-induced differentiation in a ground-based simulated microgravity model system. Rauscher murine erythroleukemia cells were grown either in tissue culture vessels at 1 x g or in the simulated microgravity environment of the NASA-designed rotating wall vessel (RWV) bioreactor. Logarithmic growth was observed under both conditions; however, the doubling time in simulated microgravity was only one-half of that seen at 1 x g. No difference in apoptosis was detected. Induction with Epo at the initiation of the culture resulted in differentiation of approximately 25% of the cells at 1 x g, consistent with our previous observations. In contrast, induction with Epo at the initiation of simulated microgravity resulted in only one-half of this degree of differentiation. Significantly, the growth of cells in simulated microgravity for 24 h prior to Epo induction inhibited the differentiation almost completely. The results suggest that the NASA RWV bioreactor may serve as a suitable ground-based microgravity simulator to model the cellular and molecular changes in erythroid cells observed in true microgravity.

Animals↗

PubMed2000

Levels of mRNAs encoding synaptic vesicle and synaptic plasma membrane proteins in the temporal cortex of elderly schizophrenic patients.

BACKGROUND: Electron microscopy and biochemical studies indicate that developmental abnormalities in synaptic organization may be present in brains of schizophrenic patients. This study determined whether these synaptic abnormalities are reflected in differential or uniform alterations in the expression of various synaptic protein genes in the left superior temporal gyrus of schizophrenic patients. METHODS: Levels of mRNAs encoding four synaptic vesicle proteins (synaptotagmin I [p65], rab3a, synaptobrevin 1, and synaptobrevin 2) and two synaptic plasma membrane proteins (syntaxin 1A and SNAP-25) were measured postmortem in the left superior temporal gyrus from elderly (58-95 years) schizophrenic patients (n = 14) and age-matched control subjects (n = 9). RESULTS: There were significant negative correlations between age and levels of synaptotagmin I (p65), rab3a, synaptobrevin 1, SNAP-25, and syntaxin 1A mRNAs in schizophrenic patients (-.692 < r < -.517,.003 < p <.030) but not in control subjects. Levels of all six synaptic mRNAs studied were increased in the younger (58-79 years) subgroup of schizophrenic patients compared to control subjects and older (80-95 years) subgroup of schizophrenic patients. CONCLUSIONS: That similar abnormalities were found for mRNAs encoding different synaptic vesicle and synaptic plasma membrane proteins suggests that they reflect overall neurodevelopmental abnormalities in synaptic connectivity in the temporal cortex of schizophrenic patients rather than changes in the number of synaptic vesicles per synapse or abnormalities in a specific synaptic function.

Aged↗

PubMed2000

Differential preservation of cognitive functions in geriatric patients with lifelong chronic schizophrenia: less impairment in reading compared with other skill areas.

BACKGROUND: Our study examined the differential performance of cognitive skills in geriatric, cognitively impaired schizophrenic patients (n = 165) with a lengthy course of institutional stay and a poor overall functional outcome. Their relative deficits were compared with a sample of healthy elderly individuals. METHODS: Schizophrenic patients were matched one-to-one with healthy individuals of the same age and education and compared on a number of measures of cognitive functioning. The schizophrenic patients' old-learning performance was also compared with their educational level only. RESULTS: Mini-Mental State Examination (Folstein et al 1975) scores of the patients were in the moderately demented range (M = 20.36), and these patients underperformed healthy control subjects by more than 1 to slightly less than 3 standard deviations on measures of memory, praxis, and verbal skills. Wide Range Achievement Test-Revised word-recognition reading scores were found to be at the 10th-grade level, although the patients on average had completed 11 years of formal education. CONCLUSIONS: These results suggest that even in schizophrenic patients with significant cognitive impairment, reading scores are relatively consistent with educational attainment. These data indicate that poor performance on measures of cognitive functioning in this population does not necessarily occur on measures of old learning.

Aged↗

PubMed2000

Clinical, cognitive and functional characteristics of long-stay patients with schizophrenia: a comparison of VA and state hospital patients.

Long-stay patients constitute a small proportion of all patients with schizophrenia, but in both VA and state psychiatric systems these patients account for a majority of the costs associated with treatment of the illness. VA and state patients would be expected to differ in several respects, including age at onset and premorbid educational status. Little additional information is available about the differences between these samples. Seventy-four long-stay male patients at a chronic state psychiatric center were compared with 50 male veterans from long-stay psychiatric facilities on positive and negative symptoms, cognitive deficits and functional status. The two samples did not differ on positive symptom severity, but the state patients had more severe negative and cognitive symptoms as well as functional deficits. Of all of the variables measured, deficit in self care was the only variable that entered a stepwise discriminant analysis. The correlation between functional and symptomatic variables was the same in both groups, and the group differences and correlations were not influenced by differences in educational status. These data indicate that VA patients may have reduced severity of functional and cognitive impairments relative to state hospital patients, but that the relationship between the different illness variables was similar in the two groups.

Aged↗

PubMed2000

The longitudinal relationship of clinical symptoms, cognitive functioning, and adaptive life in geriatric schizophrenia.

Cognitive dysfunction is increasingly being recognized as a major contributor to the adaptive impairment seen in most patients with schizophrenia. Reported here is a prospective longitudinal evaluation of the relationship between cognitive and adaptive functioning in elderly patients with schizophrenia. It was hypothesized that baseline cognitive and negative, but not positive symptoms, would be predictive of cross-sectional impairment and longitudinal outcome. Subjects were 168 elderly patients with schizophrenia, free of major neurological disorders, who were residents of a long-term psychiatric facility. Subjects were assessed at baseline and again an average of 15months later. The PANSS was used to assess the severity of symptoms of schizophrenia. Cognitive symptoms were assessed using the components of the CERAD cognitive battery. Social and adaptive functioning was assessed using the SAFE scale. Spearman correlations were determined among clinical variables, and the rank ordering of prediction of SAFE scale scores at follow-up was determined using a stepwise regression procedure. At follow-up, adaptive life skills correlated with cognitive performance and negative symptoms (Spearman rho values 0. 41-0.57, all p values <0.0001), but not positive symptoms (r=0.09, n. s.). Among cognitive tasks, verbal learning and memory were most highly correlated with adaptive skills at follow-up. These results confirm and extend previous studies that indicate that cognitive impairments are predictive, both cross-sectionally and longitudinally, of adaptive life skills in persons with schizophrenia. Negative symptoms, but not positive symptoms, were correlated with impaired adaptive skills. Taken together, these results underscore the need to develop more effective treatments for cognitive and negative symptoms in schizophrenia.

Activities of Daily Living↗

PubMed2000

A randomized controlled trial of prednisone in Alzheimer's disease. Alzheimer's Disease Cooperative Study.

BACKGROUND: Laboratory and epidemiologic studies suggest that anti-inflammatory/immunosuppressive therapy may be useful in the treatment of AD. In preliminary studies, a regimen of low to moderate dose prednisone was found to suppress peripheral inflammatory markers without adverse effects in subjects with AD. METHODS: We conducted a randomized, placebo-controlled multicenter trial to determine whether prednisone treatment slowed the rate of cognitive decline in AD. The active treatment regimen consisted of an initial dose of 20 mg of prednisone daily for 4 weeks tapered to a maintenance dose of 10 mg daily for 1 year, followed by gradual withdrawal during an additional 16 weeks. The primary outcome measure was the 1-year change in the cognitive subscale of the AD Assessment Scale. RESULTS: A total of 138 subjects were randomized to the drug and placebo groups. There was no difference in cognitive decline between the prednisone and placebo treatment groups in the primary intent-to-treat analysis, or in a secondary analysis considering completers only. Subjects treated with prednisone showed behavioral decline compared with those in the placebo group. CONCLUSION: A low-dose regimen of prednisone is not useful in the treatment of AD.

Aged↗

PubMed2000

Metabotropic glutamate receptor mRNA expression in the schizophrenic thalamus.

BACKGROUND: The central role that the thalamus plays in information processing and sensory integration suggests that its dysfunction may be a factor in the pathophysiology of schizophrenia. Glutamate is a key neurotransmitter in thalamic function, and although all aspects of thalamic glutamate neurotransmission have not been elucidated, transcripts encoding members of each family of the glutamate receptors have been identified in the thalamus. Recently, activation of group II metabotropic glutamate receptors (mGluRs) was demonstrated in rats to ameliorate the behavioral effects associated with exposure to phencyclidine, an uncompetitive NMDA receptor antagonist that can induce psychotic symptoms, suggesting the possibility of mGluR abnormalities in schizophrenia. We investigated whether expression of thalamic mGluR mRNA is altered in this illness. METHODS: We examined the expression of the transcripts encoding the mGluR1, 2, 3, 4, 5, 7, and 8 receptors in postmortem thalamic tissue samples from elderly schizophrenic and control subjects, using in situ hybridization. We identified six thalamic nuclei in each section (anterior, dorsomedial, lateral dorsal, central medial, reticular, and nuclei of the ventral tier). RESULTS: There were no differences between elderly schizophrenic and control subjects in the expression of mGluR1, 2, 3, 4, 5, 7, or 8 transcript levels in any of these six thalamic nuclei. CONCLUSIONS: mGluR mRNA expression is not abnormal in the thalamus of patients with schizophrenia. The modulatory roles proposed for mGluRs, and the potentially important relationship between mGluRs and NMDA receptors, suggest that mGluRs may be involved in the pathophysiology of schizophrenia, but this is not detectable at this level of gene expression.

Aged↗

PubMed2000

Contribution of Lewy body inclusions to dementia in patients with and without Alzheimer disease neuropathological conditions.

CONTEXT: Lewy bodies (LBs) are intraneuronal inclusions in the brain that have been increasingly recognized as neuropathological lesions with relevance not only to Parkinson disease but also to Alzheimer disease. However, the degree to which the density of LBs in the brain contributes to the severity of dementia has not been clear. OBJECTIVE: To determine the degree to which LB "burden" contributes to dementia. DESIGN: Brain specimens were examined from 273 consecutive autopsies of elderly subjects residing in a nursing home. The numbers and densities of LBs were determined in multiple brain regions, and their correlation with a measure of cognition and functional status (Clinical Dementia Rating) during the 6 months preceding death was determined. SETTING AND PATIENTS: Postmortem study of nursing home residents. RESULTS: The severity of dementia correlated significantly and positively with the density of LBs. These correlations were independent of other neuropathological disorders commonly associated with dementia, including Alzheimer disease. The density of LBs correlated significantly with dementia severity whether or not the diagnostic criteria for Alzheimer disease were met and after the contribution of classical Alzheimer disease lesions, neuritic plaques, and neurofibrillary tangles had been accounted for by partial correlation analysis. CONCLUSION: Lewy body inclusions appear to contribute significantly to cognitive deficits in the elderly in a manner that is independent of other neuropathological disorders. Arch Neurol. 2000;57:1145-1150

Aged↗

PubMed2000

Prevalence and correlates of parkinsonism in an institutionalized population of geriatric patients with chronic schizophrenia.

BACKGROUND: Geriatric patients with chronic schizophrenia are at increased risk for parkinsonism and cognitive impairment, but the relationship between the two has been insufficiently studied. OBJECTIVES: (1) To determine the prevalence of parkinsonism in a cohort of institutionalized geriatric patients with chronic schizophrenia (N=79). (2) To examine the relationship of parkinsonism to potentially relevant variables including cognitive functioning, positive and negative symptoms, sex, age, age at first hospitalization, psychopharmacological regimen and tardive dyskinesia (TD). METHOD: Tremor, rigidity and bradykinesia were rated on a five-point severity scale. Clinically significant parkinsonism was defined by the unambiguous presence of at least two of those signs. TD was assessed with the Modified Simpson Dyskinesia Scale. Schizophrenic symptoms were rated with the Positive and Negative Syndrome Scale, and cognitive functioning with the Mini-Mental State Examination and the Consortium to Establish a Registry for Alzheimer's Disease battery. RESULTS: The prevalence of parkinsonism was 19% and was significantly higher in women than in men. Age was a significant predictor of parkinsonism. Independent of age, bradykinesia was significantly correlated with MMSE, fluency and naming. Tremor, rigidity and medication status did not correlate with any cognitive variable assessed. Cognitive measures did not differ between subjects meeting and not meeting criteria for clinically significant parkinsonism. Rigidity and bradykinesia were significantly correlated with negative symptoms but no parkinsonism sign correlated with positive symptoms. Twelve subjects received ratings consistent with both TD and parkinsonism; however, no parkinsonian variable predicted the co-occurrence of TD. CONCLUSIONS: The present correlations suggest potential overlap among the neural substrates for bradykinesia, cognitive impairment and negative symptoms; however, further research is required to clarify that issue.

Age Distribution↗

PubMed2000

Has familial aggregation in Alzheimer's disease been overestimated?

Studies of the familial aggregation of Alzheimer's disease have primarily used samples ascertained from tertiary care clinics which may not be representative of many AD patients, for example those residing at geriatric nursing homes. Survival analysis was used to investigate whether estimates of familial aggregation of AD based on a clinic-based AD proband (C-AD) sample (probands: N=544; first degree relatives; N=4267) differ from one ascertained at a nursing home (NH-AD; probands: N=225; first degree relatives; N=1772). The cumulative survival from AD was significantly worse in relatives of the C-AD probands and the overall relative risk (RR) of AD in this group was greater than twice that of relatives of the NH-AD probands. However, age at onset in C-AD probands was significantly earlier than in the NH-AD group and in both groups this factor was negatively associated with familial aggregation. When, for this reason, the proband samples were matched one-to-one by age at onset, dropping those probands with no match, the two curves were close to identical and the RR for the C-AD group of relatives was 1.0 The results suggest that estimates of familial risk of AD based on C-AD samples are not applicable and overestimate the extent of increased risk for relatives of more prevalent, later onset AD probands. However, the overestimate can be explained by the typically earlier age at onset in C-AD samples as opposed to a sampling bias related to the proband's family history status per se. The relationship between onset age and familial aggregation suggests that no single estimate of the age-dependent risk (survival curve) is uniformly appropriate for relatives of AD probands.

Adult↗

PubMed2000

The Caregiver Activity Survey (CAS): longitudinal validation of an instrument that measures time spent caregiving for individuals with Alzheimer's disease.

Family members incur substantial financial costs during the course of caring for an individual with Alzheimer's disease. Much of this cost is associated with time spent in caregiving tasks, including supervision and communication with the patient, and assisting with activities of daily living. We have previously reported on the cross sectional reliability and validity of a scale that measures time spent caregiving, the Caregiver Activity Survey (CAS). This study extends our results to a longitudinal study of the validity of the instrument. Forty-four outpatients with Alzheimer's disease who lived with a primary caregiver were followed over a period of 1 year 6 months. At six month intervals, the patients were administered the Mini Mental State Exam (MMSE), Alzheimer's Disease Assessment Scale (ADAS), and the Physical Self Maintenance Scale (PSMS). Caregivers completed the CAS. Over time, the CAS correlated significantly with the MMSE (r=-0.58, p=0.000), ADAS cognitive subscale (r=0.56, p=0. 000) and PSMS (r=0.49, p=0.000). As patients declined, caregivers spent less time communicating with and more time supervising the patient. Excluding the communication item, time spent caregiving increased significantly over time. This prospective study longitudinally validates the CAS with Alzheimer's patients.

Activities of Daily Living↗