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Biomedical subjects

Kenneth L Davis

Publications and source records attributed to Kenneth L Davis.

46 records · Page 3Linked to original sources
PubMed2002

A double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia.

BACKGROUND: Despite the beneficial effects of atypical antipsychotics on cognition, these improvements will not return most schizophrenic patients to normative standards of cognitive functioning. Therefore, other treatments need to be considered. Subtle changes in cholinergic function in schizophrenic patients provide the rationale to test the effectiveness of cholinesterase inhibitors in treating cognitive impairment in schizophrenia. METHODS: Given this, a 12-week, double-blind, placebo-controlled trial of donepezil (5 mg and 10 mg) as adjunctive treatment to risperidone was conducted in a total of 36 schizophrenic patients. RESULTS: Neither the 5-mg nor 10-mg dose of donepezil produced significant improvements in any cognitive measure compared with placebo. CONCLUSIONS: It is possible that nicotinic receptor desensitization produced by chronic tobacco use in these patients rendered their nicotinic receptors refractory to the effects of increased agonist activity produced by donepezil. An alternative treatment is the allosterically potentiating ligands, which enhance the activity of (sensitize) nicotinic receptors in the presence of acetylcholine.

Adult↗
PubMed2002

Molecular and cellular evidence for an oligodendrocyte abnormality in schizophrenia.

Our previous analyses in postmortem prefrontal cortex samples from a well-characterized cohort of severely affected schizophrenics and in matched controls demonstrated decreased expression of myelin and oligodendrocyte-related genes in the disease state. This decreased expression, now replicated in independent studies, suggests that there is a disruption of oligodendrocyte function and/or a loss of oligodendrocytes in schizophrenia. In the current report, we review expression studies in schizophrenia and present data demonstrating consistently fewer oligodendrocytes in schizophrenics compared to controls. The decrease in density reached 22% (p < 0.01) in layer III of area 9 and 20% (p < 0.02) in the white matter of the superior frontal gyrus. These data, when taken together with expression studies carried out by us and by other groups, and by imaging and other microscopic studies, point to a major involvement of oligodendrocyte abnormalities in schizophrenia. Therapies modulating oligodendrocyte survival and differentiation may therefore be beneficial in schizophrenia.

Aged↗
PubMed2002

Cortical and subcortical cognitive deficits in schizophrenia: convergence of classifications based on language and memory skill areas.

Cortical and subcortical dementias have been reported to have distinct neuropsychological profiles. Previous studies of patients with schizophrenia have examined the memory-based profiles associated cortical and subcortical dementias. Although these two types of dementias have both language and memory-based profiles, the current study is the first to examine the overlap in classification associated with memory based and language based classifications. In this study, elderly (age >64 years) patients with schizophrenia (n=239) who varied in their lifetime outcome from chronic institutional care to stable community residence were tested with a neuropsychological battery that examined language and memory performance. Using a large sample of normal controls previously tested with this same assessment, normative standards for performance were developed. Schizophrenic patients were divided into cortical versus subcortical versus unimpaired groups on the basis of language and memory performance. Classification overlap ranged from a high of 30% (cortical profile) to a low of 14% (unimpaired profile). Furthermore, patients classified on the basis of verbal and memory ability areas did not differ in their performance in measures from the other ability areas. Data from a 1-year follow-up of part of the sample (n=147) suggested poor stability of the subcortical classification in particular. These data suggest that cortical versus subcortical profiles of cognitive performance in schizophrenia are inconsistent across ability areas, and are not likely to be the result of stable structural or functional brain deficits.

Aged↗
PubMed2002

Implications for altered glutamate and GABA metabolism in the dorsolateral prefrontal cortex of aged schizophrenic patients.

OBJECTIVE: Pharmacological, clinical, and postmortem studies suggest altered gamma-aminobutyric acid (GABA)-ergic and glutamatergic function in patients with schizophrenia. The dorsolateral prefrontal cortex is one key locus of abnormality. The precise neurochemical mechanisms underlying neurotransmitter alterations, such as hypoglutamatergia or GABA dysfunction, are not well understood. This study investigated key biochemical elements of GABA and glutamate metabolism in brain specimens from schizophrenic patients. The activities of nine principal GABA and glutamate-associated metabolic enzymes were measured concurrently in the dorsolateral prefrontal cortex of antemortem-assessed and neuropathologically characterized schizophrenic and comparison subjects. METHOD: Postmortem dorsolateral prefrontal cortex specimens from schizophrenia, Alzheimer's disease, and normal nonpsychiatric comparison subjects were assayed to determine activities of the principal glutamate and GABA-metabolizing enzymes glutamine synthetase, glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, phosphate-activated glutaminase, alanine aminotransferase, aspartate aminotransferase, glutamic acid decarboxylase, GABA-transaminase, and succinic semialdehyde dehydrogenase. RESULTS: Glutamic acid decarboxylase activities were twofold greater and phosphate-activated glutaminase activities were fourfold greater in the schizophrenic group than in the comparison group. Differences in postmortem interval, tissue pH, inhibition of phosphate-activated glutaminase, and medication effects could not account for the differences. Differences in phosphate-activated glutaminase and glutamic acid decarboxylase activities in equivalent specimens from Alzheimer's patients were not observed. The activities of the remaining enzymes were unchanged. CONCLUSIONS: Greater phosphate-activated glutaminase and glutamic acid decarboxylase activities, specific to schizophrenia patients, provide additional biochemical evidence that dorsolateral prefrontal cortex glutamate and GABA metabolism is altered in schizophrenic subjects. These greater activities are consistent with models of a dysregulated glutamatergic/GABA-ergic state in schizophrenia.

Age Factors↗
PubMed2002

Correlates of change in functional status of institutionalized geriatric schizophrenic patients: focus on medical comorbidity.

OBJECTIVE: Impairment in basic self-care skills is common in patients with schizophrenia and is even more severe in elderly patients with a chronic course of institutional care. While cognitive impairment has proven to be a major predictor of overall functional deficit in schizophrenia, other potential factors, such as medical comorbidity, need to be considered. METHOD: Geriatric institutionalized schizophrenic patients (N=124) were assessed three times over 4 years to determine levels of positive and negative symptoms, impairment in activities of daily living, impairment in cognitive functioning, and medical problems. Path analysis was used to determine which variables best predicted changes in self-care functions. RESULTS: Functional status, negative symptoms, cognitive functions, and health status all significantly worsened during the follow-up. The path analyses showed that change in health status did not predict change in activities of daily living after the analysis accounted for negative symptoms and cognitive functions. DISCUSSION: The results highlight the relative importance of cognitive impairments in the functional impairments of older schizophrenic patients with increased medical burden.

Activities of Daily Living↗
PubMed2002

Cognitive assessment of geriatric schizophrenic patients with severe impairment.

There is evidence that some elderly patients with chronic schizophrenia experience marked impairments in cognitive functioning. Assessment of these patients may be difficult with traditional neuropsychological measures. The purpose of the present study was to determine if cognitive functioning could be validly assessed with the Alzheimer's Disease Assessment Scale-Late Version Cognitive factor score (ADAS-L Cog) in patients whose scores on the Mini-Mental State Examination (MMSE) reflect profound cognitive impairment. Patients with MMSE scores from 0 to 10 were selected from a larger database. Neuropsychological instruments designed for the assessment of mild to moderate dementia were found to be inadequate in this profoundly impaired population, due to floor effects. In contrast, there was a significant relationship between ADAS-L scores and several criterion measures, including the MMSE (R=-.71, P<.001), the Social Adaptive Functions Evaluation (SAFE) social functions scale (R=.47, P<.001), and the negative symptom total score of the Positive and Negative Syndrome Scale (PANSS) (R=.412, P<.001). The MMSE was somewhat less strongly correlated with both social functions (R=-.401, P<.001) and the negative symptom total score of the PANSS (R=-.366, P<.001). These results suggest that cognition can be reliably and validly assessed with instruments such as the ADAS-L that are designed for the assessment of severely impaired patients.

Journal Article↗
PubMedDate not supplied

The course of functional decline in geriatric patients with schizophrenia: cognitive-functional and clinical symptoms as determinants of change.

OBJECTIVE: Authors sought to use a cognitive assessment instrument validated for assessing low-functioning patients to broaden knowledge about the rate and correlates of functional decline. METHODS: Patients were examined across a wide range of baseline cognitive and functional status, and changes in cognitive and functional status were examined. A group of 424 elderly patients with schizophrenia were followed up over a 6-year period; 280 of these manifested severe cognitive impairment at baseline. Patients were examined with an instrument designed for cognitive and functional assessment of severe cognitive impairment: the Alzheimer's Disease Assessment Scale-Late (ADAS-L). RESULTS: Patients with higher and lower baseline scores manifested equivalent declines in the ADAS-L cognitive subscale, but differences in decline on basic activities of daily living. Random-effects regression analysis indicated that functional changes were significantly correlated with cognitive changes for the sample as whole and that cognitive changes were the best predictor of changes in functional status over time. Baseline cognitive status was not a statistically significant covariate for functional change, nor was the course of negative symptoms over the follow-up period. CONCLUSIONS: Cognitive change appears very similar in magnitude across older, poor-outcome patients with different baselines of cognitive impairment. In contrast, functional decline was limited to patients with lower levels of functioning at baseline. These findings suggest that cognitive thresholds for impairments in different aspects of functional status may exist in patients with schizophrenia. Basic activities of daily living decline only in patients with very low levels of baseline cognitive functioning.

Aged↗
PubMedDate not supplied

Biological markers in Alzheimer disease.

Biological markers are important tools in identifying predisposing factors to disease, as diagnostic tests, and in monitoring disease progression. Alzheimer disease is believed to have a long preclinical phase, followed by mild cognitive impairment, and, finally, dementia. Detecting alterable predisposing factors or identifying patients in preclinical or early-stage illness offers the greatest potential to modifying disease course. The authors focus on: 1) predisposing factors, such as genetic risk factors and homocysteine; 2) laboratory markers, such as amyloid beta and tau protein; and 3) diagnostic markers, such as structural and functional neuroimaging. Many markers have been tested but have not been confirmed in subsequent studies. Other tests require complex and expensive laboratory evaluation or expertise, thereby limiting their use at present. Still others are markers only useful in later-stage illness. Nonetheless, the search for markers has increased our understanding of the biology of illness and has led to exciting new directions, with diagnostic as well as treatment implications.

Aged↗
PubMedDate not supplied

Cognitive burden and excess Lewy-body pathology in the Lewy-body variant of Alzheimer disease.

OBJECTIVES: Authors compared the degrees of cognitive deficit among individuals with Alzheimer disease (AD), the Lewy-body variant of AD (LBV), and "pure" dementia with Lewy bodies (DLB); and compared cortical Lewy body (LB) counts in LBV versus DLB and neuritic plaque and neurofibrillary tangle severity in LBV versus AD. METHODS: Authors examined brain specimens from consecutive autopsies of elderly nursing home subjects. Numbers and densities of plaques, Lewy bodies, and tangle severity were determined in multiple cortical regions, and demographic and clinical variables were compared among the three groups. RESULTS: The three groups did not differ in demographic or clinical variables. The LBV group was significantly more impaired than the other groups. Cortical LB counts were significantly higher in LBV than in DLB. There was no evidence of increased plaque or tangle severity in LBV than in AD. CONCLUSION: The co-occurrence of AD and LB pathology is associated with higher numbers of LBs and more severe dementia than when classical AD or LB lesions occur alone.

Aged↗