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K L Davis

Publications and source records attributed to K L Davis.

At least 55 records · Page 3Linked to original sources
PubMed1999

The role of norepinephrine in the pathophysiology of cognitive disorders: potential applications to the treatment of cognitive dysfunction in schizophrenia and Alzheimer's disease.

The role of noradrenergic neurotransmission in normal cognitive functions has been extensively investigated, however, the involvement of noradrenergic functions in the cognitive impairment associated with schizophrenia and Alzheimer's disease has not been as intensively considered. The limited ability of atypical antipsychotics to treat the cognitive impairment of schizophrenia, and cholinomimetics to treat the cognitive impairment of Alzheimer's disease, may be related to the influence of a multiplicity of neurotransmitter abnormalities including noradrenergic dysfunction, which these treatments do not address. The evidence of noradrenergic dysfunction occurring concomitantly with dopamine dysfunction in schizophrenia and acetylcholine dysfunction in Alzheimer's disease supports therapeutic approaches using noradrenergic drugs in combination with neuroleptics and cholinesterase inhibitors, respectively, to enhance the treatment of cognitive impairment. Given the results of animal and human studies, it appears that alpha-2A agonists may be the optimal choice for this purpose.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1999

Cognitive and functional changes with aging in schizophrenia.

The variation in functional outcome in schizophrenia appears to be exaggerated in late life. The cognitive and functional deficits commonly seen in younger schizophrenic patients appear to worsen in some cases in late life, while others patients appear to have a stable course of illness without functional decline, and still other patients have been reported to have essentially no residual symptoms in their later years. Cognitive and functional deficits appear to worsen more significantly in patients with a lifetime course of severe functional deficit. Despite the profound functional and cognitive deficits in these patients, neuropathologic studies have found no evidence of typical causes of severe cognitive impairments. This paper reviews the current findings on cognitive and functional changes in aging in schizophrenia, with a specific focus on patients with a poor lifetime functional outcome.

Activities of Daily Living↗
PubMed1999

An erythropoietin fusion protein comprised of identical repeating domains exhibits enhanced biological properties.

The hematopoietic growth factor erythropoietin (Epo) initiates its intracellular signaling cascade by binding to and inducing the homodimerization of two identical receptor molecules. We have now constructed and expressed in COS cells a cDNA encoding a fusion protein consisting of two complete human Epo domains linked in tandem by a 17-amino acid flexible peptide. On SDS-polyacrylamide gel electrophoresis, the Epo-Epo fusion protein migrated as a broad band with an average apparent molecular mass of 76 kDa, slightly more than twice the average apparent molecular mass of Epo, 37 kDa. Enzymatic N-deglycosylation resulted in an Epo-Epo species that migrated on SDS-polyacrylamide gel electrophoresis as a narrow band with an average apparent molecular mass of 39 kDa. The specific activity of the Epo-Epo fusion protein in vitro (1,007 IU/microgram; 76 IU/pmol) was significantly greater than that of Epo (352 IU/microgram; 13 IU/pmol). Moreover, secretion of Epo-Epo by COS cells was 8-fold greater than that of Epo. Subcutaneous administration of a single dose of Epo-Epo to mice resulted in a significant increase in red blood cell production within 7 days. In contrast, administration of an equivalent dose of conventional recombinant Epo was without effect. The pharmacokinetic behavior of Epo-Epo differed significantly from that of Epo. The results suggest that Epo-Epo may have important biological and therapeutic advantages.

Amidohydrolases↗
PubMed1999

Genetic epidemiological study of maternal and paternal transmission of Alzheimer's disease.

Recent evidence for mitochondrial mutations associated with Alzheimers disease (AD) suggests the possibility of maternal transmission of this illness. We investigated this hypothesis by examining, in a variety of ways, the risk of a primary progressive dementia (PPD) in the parents (n = 650) and siblings (n = 1,220) of 325 AD probands. The results did not support maternal transmission in AD: The mothers of AD probands were not at greater risk of PPD than the fathers or the sisters of AD probands; the offspring of affected mothers were not at greater risk than the offspring of affected fathers or families with no affected parent; and, after selecting those proband families with evidence for increased familial loading, such families did not more frequently have affected mothers than fathers. In contrast, the cumulative risk of PPD in fathers of AD probands, while similar to that of mothers, was significantly increased over the brothers of AD probands. In addition, the cumulative risk curve of PPD in the offspring of affected fathers was significantly higher than the offspring of no affected parents. While no evidence for maternal transmission in AD was observed, unexpectedly, we did find evidence of increased paternal transmission.

Adult↗
PubMed1999

Regulated expression and functional role of the transcription factor CHOP (GADD153) in erythroid growth and differentiation.

The hematopoietic growth factor erythropoietin (Epo) triggers changes in the expression of genes that encode important regulators of erythroid cell growth and differentiation. We now report that Epo markedly upregulates chop (gadd153) expression and that this transcription factor plays a role in erythropoiesis. Using a differential hybridization assay, we isolated a full-length cDNA of chop as an Epo upregulated gene in Rauscher murine erythroleukemia cells. RNase protection assays demonstrated that Epo or dimethyl sulfoxide induction increased steady-state mRNA levels 10- to 20-fold after 24 to 48 hours. Western blot analysis confirmed a marked increase in CHOP protein. Among the other c/ebp family members, only c/ebp beta was also upregulated during erythroid differentiation. Among normal hematopoietic cells examined, steady-state mRNA levels were highest in erythroid cells, with levels peaking during terminal differentiation. Transient overexpression of chop in Rauscher cells resulted in a significant increase in Epo- or dimethyl sulfoxide (DMSO)-induced hemoglobinization, further linking chop upregulation to erythroid differentiation. Artificial downregulation of chop in normal murine bone marrow cells with antisense oligodeoxynucleotides inhibited colony-forming unit-erythroid (CFU-E)-derived colony growth in a concentration-dependent manner. Burst-forming unit-erythroid (BFU-E)-derived colony growth was not affected. Using a Far Western type of analysis, we detected several potential CHOP binding partners among the nuclear proteins of Rauscher cells. Importantly, the number and relative abundance of these proteins changed with differentiation. The results strongly suggest that CHOP plays a role in erythropoiesis, possibly through interactions with both C/EBP and non-C/EBP family members.

Animals↗
PubMed1999

Genetic antecedents of dopamine dysfunction in schizophrenia.

BACKGROUND: Relatives of schizophrenic probands frequently manifest attenuated features of this illness including the negative symptoms and the milder positive psychotic symptoms. These two symptom dimensions are hypothesized to be associated with decreased and increased brain dopamine (DA) functions, respectively, raising the possibility that DA abnormalities may be present in the relatives of schizophrenic probands. METHODS: Plasma homovanillic acid (HVA), the major DA metabolite and an indicator of brain DA activity, was measured in nonpsychotic, physically healthy first-degree relatives (n = 55) of schizophrenic probands and in normal subjects (n = 20) without a family history of schizophrenia. RESULTS: Plasma HVA inversely correlated with negative symptoms and positively correlated with attenuated positive symptoms. Also, relatives had decreased plasma HVA compared to normal subjects, consistent with the fact that these relatives are characterized by negative symptoms. These findings were not related to major peripheral factors that could affect plasma HVA suggesting that the findings may reflect changes in brain DA activity. CONCLUSIONS: Negative symptoms indicating a genetic diathesis to schizophrenia in relatives may have a biologic basis in reduced DA activity and the DA dysfunction of schizophrenia may have genetic antecedents. This opens an important new avenue for further study of DA in this illness.

Adult↗
PubMed1999

Cholinergic markers in elderly patients with early signs of Alzheimer disease.

CONTEXT: A central tenet of Alzheimer disease (AD) is the loss of cortical cholinergic function and cholinergic markers in postmortem brain specimens. Whether these profound deficits in cholinergic markers found in end-stage patients are also found in patients with much earlier disease is not known. OBJECTIVE: To determine whether cholinergic deficits in AD precede, follow, or occur in synchrony with the earliest signs of cognitive deterioration. DESIGN, SETTING, AND PATIENTS: Postmortem study of nursing home residents with Clinical Dementia Rating (CDR) Scale scores of 0.0 to 2.0 and 4.0 to 5.0 who underwent autopsy between 1986 and 1997, comparing the activity of the cholinergic marker enzymes in the cortices of 66 elderly subjects with no (CDR score = 0.0; n = 18), questionable (CDR score = 0.5; n = 11), mild (CDR score = 1.0; n = 22), or moderate (CDR score = 2.0; n = 15) dementia vs subjects with severe dementia (CDR score = 4.0-5.0; n = 15). MAIN OUTCOME MEASURES: Activity of the cholinergic marker enzymes choline acetyltransferase and acetylcholinesterase in 9 neocortical brain regions. RESULTS: The activity of choline acetyltransferase and acetylcholinesterase in 9 neocortical brain regions did not differ significantly in subjects with CDR scores of 0.0 to 2.0, but was significantly lower in subjects with severe dementia (CDR score = 4.0-5.0). Choline acetyltransferase levels were significantly correlated with severity of neuropathological lesions of AD, as measured by density of neuritic plaques and neurofibrillary tangles. CONCLUSIONS: Although neocortical cholinergic deficits are characteristic of severely demented AD patients, in this study, cholinergic deficits were not apparent in individuals with mild AD and were not present until relatively late in the course of the disease. These results suggest that patients with more severe disease should be a target for cholinergic treatment.

Acetylcholinesterase↗
PubMed1999

Convergence of cognitive and adaptive decline in late-life schizophrenia.

Cognitive impairment has proven to be a major predictor of overall functional deficit in schizophrenia. Despite the significant impairments seen on the part of many patients with schizophrenia that implicate decline at some point in time, there have been no longitudinal studies of adaptive decline in patients with schizophrenia. In this study, 57 geriatric patients with chronic schizophrenia were examined with measures of clinical symptoms, cognitive impairments, and adaptive functioning while living in a chronic psychiatric hospital and followed up an average of two and a half years after their referral to nursing home care. Cognitive functioning and adaptive functioning both declined over the follow-up period, whereas there was no change in schizophrenic symptoms. Changes in cognitive functioning accounted for 25% of the variance in adaptive decline, whereas the baseline severity of cognitive impairment and schizophrenia symptoms were uncorrelated with adaptive decline. These data indicate that cognitive decline may predict deterioration in overall functional status and imply that treatment of cognitive impairment might have a beneficial effect on global functional status.

Adaptation, Psychological↗
PubMed1999

Cognitive decline in late-life schizophrenia: a longitudinal study of geriatric chronically hospitalized patients.

BACKGROUND: Geriatric schizophrenic patients with a chronic course of institutionalization manifest cognitive and functional impairments that implicate decline at some time point after the onset of illness. The rate of change in cognitive and functional status in these patients has not yet been identified with a longitudinal study. METHODS: Three hundred and twenty-six schizophrenic patients entered a 30-month follow-up study with two separate assessments of the patients. Overall functional and cognitive status was indexed with the Clinical Dementia Rating (CDR). Survival analysis was used to examine changes in cognitive and functional status, including worsening for the less impaired patients and improvements on the part of more impaired patients. RESULTS: Approximately 30% of the patients who had baseline scores in the less impaired range manifested a worsening of their CDR ratings to a score of 2.0 (moderate) or more severe, whereas only 7% of the sample with lower scores at baseline appeared to improve in their functioning. Several characteristics of the patients at baseline assessment predicted increased risk for cognitive and functional decline, including lower levels of education, older age, and more severe positive symptoms. CONCLUSIONS: Cognitive and functional decline can be detected in a short-term follow-up in a subset of geriatric long-stay patients with schizophrenia. This decline appears distributed across patients and not due to the presence of progressive degenerative dementing conditions. Later research will have to identify the causes of this decline, possibly on the basis of the risk factors identified in this study.

Aged↗
PubMed1999

Pharmacologic strategies for augmenting cognitive performance in schizophrenia.

There is recognition that the cognitive symptoms of schizophrenia have the most substantial impact on illness outcome. Domains of cognition reported to be significantly affected include serial learning, executive function, vigilance, and distractibility, to name a few. Dopamine activity at D1 receptors mediates many cognitive processes subserved by the prefrontal cortex (PFC), particularly working memory. The number of D1 receptors in the PFC is decreased in schizophrenics and is unaffected by chronic administration of typical neuroleptics. Therefore, medications that increase dopamine in the PFC, such as atypical neuroleptics, or that directly activate the D1 receptor may prove useful in the remediation of prefrontal-dependent cognitive deficits in schizophrenia. Decreased levels of cortical norepinephrine (NE) are associated with impaired learning and working memory in animal models, and can be reversed by drugs that restore NE activity. More specifically, alpha-2 adrenergic receptor agonists have been particularly effective in improving delayed response performance in young monkeys with localized 6-hydroxydopamine lesions in the PFC. Furthermore, human postmortem studies have demonstrated decreased NE in the frontal cortex of demented schizophrenic patients. Therefore, alpha-2 receptor agonists hold promise as drugs to improve cognitive performance on tasks dependent upon PFC function in schizophrenics. Finally, the finding that cortical choline acetyl transferase activity correlates with Clinical Dementia Rating scores in schizophrenic patients and that cholinomimetic drugs enhance cognition in healthy subjects suggests that cholinergic drugs may also treat cognitive symptoms in schizophrenia. Two potential types of cholinomimetics for use in schizophrenics are the acetylcholinesterase inhibitors and M1/M4 muscarinic agonists, both of which increase cortical cholinergic activity.

Acetylcholine↗
PubMed1999

Neurofibrillary tangles in nondemented elderly subjects and mild Alzheimer disease.

BACKGROUND: The relationship between neuropathological lesions and mild, "preclinical," cognitive impairments of Alzheimer disease is poorly understood. Identification of the lesions that are most closely associated with the earliest symptoms of Alzheimer disease is crucial to the understanding of the disease process and the development of treatment strategies to affect its progression. DESIGN AND MAIN OUTCOME MEASURES: We examined the extent of neurofibrillary tangles (NFTs) in 4 neocortical regions, the hippocampus, the entorhinal cortex, and the amygdala in 65 elderly subjects with no dementia, questionable dementia, mild dementia, or moderate dementia as assessed using the Clinical Dementia Rating Scale (CDR). SETTING AND PATIENTS: Postmortem study of nursing home residents. RESULTS: Neurofibrillary tangles were present in the entorhinal cortex and the hippocampus of all subjects, including those without cognitive deficits. Neocortical NFTs were mostly absent in the nondemented (CDR score, 0.0) subjects. The density of NFTs in the questionably demented (CDR score, 0.5) subjects was not significantly increased (P>.20) relative to the nondemented group in any of the brain regions studied. Significant increases (P<.04) in NFT density become apparent first in the amygdala and the temporal cortex in subjects rated to be mildly impaired (CDR score, 1.0). By the time that cognitive impairments were judged to be moderately severe (CDR score, 2.0), all regions of the brain examined, except for the occipital cortex, were significantly (P<.05) involved. CONCLUSIONS: Some NFTs are present in the entorhinal cortex and hippocampus of most elderly individuals irrespective of their cognitive status, but the density of NFTs increases as a function of dementia severity.

Aged↗
PubMed1999

Neuropeptide abnormalities in patients with early Alzheimer disease.

BACKGROUND: Deficits in somatostatin-like immunoreactivity (SLI) and corticotropin-releasing factor immunoreactivity (CRF-IR) are well recognized as prominent neurochemical deficits in Alzheimer disease (AD). The question of whether these profound neuropeptidergic deficits found in patients with end-stage disease extend into those with much earlier disease is relatively unanswered. To determine the relation between level of SLI and CRF-IR in different cerebrocortical regions to the earliest signs of cognitive deterioration in AD. METHODS: We examined SLI and CRF-IR levels in 9 neocortical brain regions of 66 elderly patients in a postmortem study of nursing home residents who had either no significant neuropathologic lesions or lesions associated only with AD. Patients were assessed by the Clinical Dementia Rating scale (CDR) to have no dementia or questionable, mild, or moderate dementia, and were compared with 15 patients with severe dementia. RESULTS: Both CRF-IR and SLI were significantly reduced in the cortices of patients with the most severe dementia, but only the levels of CRF-IR were reduced in those with mild (CDR = 1.0) and moderate dementia (CDR = 2.0). Levels of CRF-IR and SLI correlated significantly with CDR, but this correlation was more robust for CRF-IR and persisted even when severely cognitively impaired patients were eliminated from analysis. CONCLUSIONS: Although SLI and CRF-IR levels are significantly reduced in patients with severe dementia, only CRF-IR is reduced significantly in the cortices of those with mild dementia. Thus, CRF-IR can serve as a potential neurochemical marker of early dementia and possibly early AD.

Aged↗
PubMed1999

The impact of behavioral impairment of functional ability in Alzheimer's disease.

This study sought to determine the relationship between behavioral disturbance and functional status in a longitudinally studied sample of patients with Alzheimer's disease (AD). One hundred and forty-nine patients meeting NINCDS-ADRDA criteria for probable AD were followed for an average of 37.3 months, with follow-up assessments every 6 months. Subjects were seen at the Alzheimer's Disease Research Center clinics at the Mt Sinai Medical Center, New York, and the Veterans Affairs Medical Center, Bronx, New York. Measures included the Physical and Self-Maintenance Scale (PSMS) and Instrumental Activities of Daily Living Scale (IADLS) of Lawton and Brody and the cognitive and non-cognitive subscales of the Alzheimer's Disease Assessment Scale (ADAS). For each patient the assessment at which they had their most severe non-cognitive symptoms as measured by the non-cognitive part of the ADAS (ADAS-NC) was determined. ADAS-NC scores at that assessment were correlated with IADLS and PSMS scores at the same assessment and at the next assessment 6 months later. While there was some modest association of ADAS-NC scores with functional impairment using pairwise correlation coefficients, none of the correlations remained significant when the severity of cognitive impairment was controlled statistically. Findings were not significantly changed when drug status was controlled. These results suggest that behavioral disturbance, while very troubling to caregivers and patients, does not substantially worsen functional ability beyond the contribution of cognitive impairment in AD. Together with previous results indicating that non-cognitive symptoms in AD are episodic and fluctuating rather than progressive, the present data suggest that interventions for non-cognitive disturbances in AD should be viewed as ways to increase patient comfort, safety and ease of care and not as ways to improve functional autonomy. The latter can be achieved only by improving the progressive cognitive deficits of AD.

Activities of Daily Living↗
PubMed1999

Variation in tau, the time constant for isovolumic relaxation, along the left ventricular base-to-apex axis.

Tau (tau), the time constant for isovolumic relaxation, is often used as a measure of cardiac diastolic function. However, several methods of calculating tau have been published which may produce different results and, thereby, different conclusions. The purpose of this study was to determine if the method of tau calculation effects the results when left ventricular pressure (LVP) is measured at different positions along the base-to-apex axis. In 16 dogs, we measured LVP at 6 positions along the base-to-apex axis. We calculated tau using three different methods: 1) a monoexponential model (P(t) = [P0-Pasym]eAt + Pasym, where t = time, P0 = LVP at t = 0, Pasym is asymptotic pressure as t-->infinity, A is -1/tau) with a zero asymptote 2) a monoexponential model with a variable asymptote in which the monoexponential decay equation is differentiated with respect to time and substituted into the original equation so that dP/dt vs. LVP is A (-1/tau), and 3) a monoexponential decay model with variable asymptote in which Pasym and A are varied until the best fit line is reached by minimizing the residual sum of squares. When tau is calculated using method 1, tau measured at the LV base is 98.01% +/- 8.85% of tau at the apex. If calculated using method 2, tau measured at the LV base was 75.46 +/- 39.4% of tau measured at the apex. When method 3 is used for tau calculations, base tau increases to 117.76 +/- 4.91% of the apical tau. We conclude: 1) the method used to calculate tau will effect the results and, thus, conclusions drawn from tau data. 2) When using Method 3, which appears to be the best method for tau calculation, tau increases at the LV base compared to the apex.

Animals↗
PubMed1999

Neurobehavioral deficits in Persian Gulf veterans: evidence from a population-based study. Portland Environmental Hazards Research Center.

Reports of low-concentration nerve gas exposures during the Persian Gulf War have spurred concern about possible health consequences and refocused interest on the symptoms reported by many returning military veterans. The Portland Environmental Hazards Research Center is studying veterans from the Northwest USA who report persistent, unexplained "Persian Gulf" symptoms (cases) or who do not report those symptoms (controls). Of the first 101 veterans studied, cases differed substantially from controls on a broad range of psychological tests indicative of increased distress. A subgroup of cases was identified with objective deficits on neurobehavioral tests of memory, attention, and response speed.

Adult↗