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Biomedical subjects

C M Clark

Publications and source records attributed to C M Clark.

At least 19 recordsLinked to original sources
PubMed2002

A videotaped CIBIC for dementia patients: validity and reliability in a simulated clinical trial.

BACKGROUND: The global impression of a clinician is an Food and Drug Administration--mandated primary outcome measure for clinical trials in dementia. Reliability and validity of these measures are not well established. METHODS: A videotaped version of the Clinician's Interview Based Impression of Change (CIBIC) was evaluated. Raters were informed that the videotaped interviews were taken at baseline and 6 to 12 months later, when in fact half of the interviews were shown in reverse order. Ratings on "true order" interviews were compared with ratings on "reverse order" interviews. In addition, ratings by neurologists experienced in dementia were compared with those of less experienced raters. RESULTS: Inter-rater reliability of the neurologists was poor when measured by absolute agreement on a 7-point scale (kappa = 0.18). With a less stringent 3-point scale (better, worse, or unchanged), inter-rater reliability was significantly better for the true order videos (kappa = 0.51) than for the reversed order videos (kappa = 0.12). Validity also was reduced in the reverse order group: neurologists rated 90% of subjects correctly in the "true order" group and 63% correctly in the "reversed order" group. The inter-rater reliability of the neurologists was greater than the less experienced raters, but the validity of the neurologists' ratings was only marginally better. CONCLUSIONS: The reliability and validity of the videotape CIBIC are reasonable when patients follow the expected course of gradual decline, but are poor when patients appear to improve. These findings suggest that global assessments should be modified as outcome measures in clinical trials with patients with dementia.

Aged↗
PubMed2001

Positron emission tomography in evaluation of dementia: Regional brain metabolism and long-term outcome.

CONTEXT: Deficits in cerebral glucose utilization have been identified in patients with cognitive dysfunction attributed to various disease processes, but their prognostic and diagnostic value remains to be defined. OBJECTIVE: To assess the sensitivity and specificity with which cerebral metabolic patterns at a single point in time forecast subsequent documentation of progressive dementia. DESIGN, SETTING, AND PATIENTS: Positron emission tomography (PET) studies of [(18)F]fluorodeoxyglucose in 146 patients undergoing evaluation for dementia with at least 2 years' follow-up for disease progression at the University of California, Los Angeles, from 1991 to 2000, and PET studies in 138 patients undergoing evaluation for dementia at an international consortium of facilities, with histopathological diagnoses an average of 2.9 years later, conducted from 1984 to 2000. MAIN OUTCOME MEASURES: Regional distribution of [(18)F]fluorodeoxyglucose in each patient, classified by criteria established a priori as positive or negative for presence of a progressive neurodegenerative disease in general and of Alzheimer disease (AD) specifically, compared with results of longitudinal or neuropathologic analyses. RESULTS: Progressive dementia was detected by PET with a sensitivity of 93% (191/206) and a specificity of 76% (59/78). Among patients with neuropathologically based diagnoses, PET identified patients with AD and patients with any neurodegenerative disease with a sensitivity of 94% and specificities of 73% and 78%, respectively. The negative likelihood ratio of experiencing a progressive vs nonprogressive course over the several years following a single negative brain PET scan was 0.10 (95% confidence interval, 0.06-0.16), and the initial pattern of cerebral metabolism was significantly associated with the subsequent course of progression overall (P<.001). CONCLUSION: In patients presenting with cognitive symptoms of dementia, regional brain metabolism was a sensitive indicator of AD and of neurodegenerative disease in general. A negative PET scan indicated that pathologic progression of cognitive impairment during the mean 3-year follow-up was unlikely to occur.

Aged↗
PubMed2001

Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia.

Dementia lacking distinctive histopathology (DLDH) or frontotemporal lobe degeneration (FTLD) is the most common neuropathological diagnosis for sporadic frontotemporal dementias (FTDs). The hallmarks of DLDH are neuron loss and gliosis in the absence of any disease-specific brain lesion. Similar brain pathology is also seen in a familial FTD pedigree known as hereditary dysphasic disinhibition dementia 2 (HDDD2). Abnormality in the function or isoform composition of the microtubule binding protein tau is a prominent feature in the brains of many patients with sporadic and hereditary FTDs. Therefore, we studied the tau protein in different brain regions from DLDH and HDDD2 patients. Our results indicate that a selective loss of all six tau isoforms, but not tau mRNA, occurs in these brains compared to normal control and Alzheimer's disease brains. Loss of tau protein was identified by Western blot analysis of protein extracts from DLDH and HDDD2 brains in regions both with and without neuronal degeneration. Functionally, this loss of tau protein may be equivalent to pathogenic mutations in the tau gene identified in familial FTD with parkinsonism linked to chromosome 17 (FTDP-17). Thus, DLDH and HDDD2 are novel tauopathies with a unique mechanism of pathogenesis. The presence of tau mRNA in these brains suggests that the level of tau protein may be controlled posttranscriptionally, at the level of either translation or mRNA stability.

Aged↗
PubMed2001

The relationship between caregivers' global ratings of Alzheimer's disease patients' quality of life, disease severity, and the caregiving experience.

OBJECTIVES: To compare caregivers' ratings of Alzheimer's disease (AD) patients' global quality of life (QOL) using direct assessments and substituted judgments, and to identify qualities of the patients and their caregivers that are associated with these QOL assessments. DESIGN: Cross-sectional interviews. SETTING: A university-based Memory Disorders Clinic. PARTICIPANTS: Forty primary caregivers of AD patients. MEASUREMENTS: Direct scaling of overall quality of life (poor, fair, good, very good, or excellent) and measures of dementia severity, the caregiving experience, and patient and caregiver demographics. RESULTS: The majority of patients had mild (n = 20) or moderate (n = 11) AD. Caregivers' direct assessments of patient QOL were poor (5%, n = 2), fair (28%, n = 11), good (40%, n = 16), very good (20%, n = 8), and excellent (8%, n = 3). Twenty-one (52.5%) of the caregivers rated the patient's QOL the same as they thought the patient would; 12 (30.0%) rated the patient's QOL worse; and seven (17.5%) rated the patient's QOL better. Agreement between the two ratings was fair to moderate. Bivariate analyses showed that lower ratings of caregivers' direct assessments of patient QOL were associated with decreasing ratings of patient mental health and increasing dementia severity, caregiver burden, and caregiver depression. Multivariate models showed burden to be the significant predictor of caregivers' rating of patient QOL and the subscale measuring the caregivers' distress at controlling patient behavior had the strongest association with QOL. Lower ratings of substituted judgment assessments of patient QOL were associated with lower caregiver ratings of the patient's mental health. CONCLUSIONS: Nearly one-half of the caregivers of patients with predominantly mild to moderate AD assess a patient's QOL differently than they believe the patient would. Dementia severity and the caregiver's experiences of depression and burden negatively affect caregivers' assessments of QOL. These results provide a compelling reason why clinicians should take the time to screen for and address caregiver depression and burden and problematic patient behaviors.

Adult↗
PubMed2001

Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin.

OBJECTIVE: To determine the safety and efficacy of the long-acting analog insulin glargine compared with NPH insulin in patients with type 2 diabetes who were previously treated with insulin alone. RESEARCH DESIGN AND METHODS: A total of 518 subjects with type 2 diabetes who were receiving NPH insulin with or without regular insulin for postprandial control were randomized to receive insulin glargine (HOE 901) once daily (n = 259) or NPH insulin once or twice daily in = 259) for 28 weeks in an open-label, multicenter trial. Doses were adjusted to obtain target fasting glucose <6.7 mmol/l. At study end point, the median total daily insulin dose in both treatment groups was 0.75 IU/kg. RESULTS: The treatment groups showed similar improvements in HbA1c from baseline to end point on intent-to-treat analysis. The mean change (means +/- SD) in HbA1c from baseline to end point was similar in the insulin glargine group (-0.41 +/- 0.1%) and the NPH group (-0.59 +/- 0.1%) after patients began with an average baseline HbA1c of approximately 8.5%. The treatments were associated with similar reductions in fasting glucose levels. Overall, mild symptomatic hypoglycemia was similar in insulin glargine subjects (61.4%) and NPH insulin subjects (66.%) However, nocturnal hypoglycemia in the insulin glargine group was reduced by 25% during the treatment period after the dose-titration phase(26.5 vs. 35.5%, P = 0.0136). Subjects in the insulin glargine group experienced less weight gain than those in the NPH group (0.4 vs. 1.4 kg, P < 0.0007). CONCLUSIONS: In patients with type 2 diabetes, once-daily bedtime insulin glargine is as effective as once- or twice-daily NPH in improving and maintaining glycemic control. In addition, insulin glargine deonstrates a lower risk of nocturnal hypoglycemia and less weight gain compared with NPH insulin.

Blood Glucose↗
PubMed2001

A systematic approach to risk stratification and intervention within a managed care environment improves diabetes outcomes and patient satisfaction.

OBJECTIVE: To determine whether a comprehensive diabetes management program that included risk stratification and social marketing would improve clinical outcomes and patient satisfaction within a managed care organization (MCO). RESEARCH DESIGN AND METHODS: The 12-month prospective trial was conducted at primary care clinics within a MCO and involved 370 adults with diabetes. Measurements included 1) the frequency of dilated eye and foot examinations, microalbuminuria assessment, blood pressure measurement, lipid profile, and HbA(1c) measurement; 2) changes in blood pressure, lipid levels, and HbA(1c) levels; and 3) changes in patient satisfaction. RESULTS: Complete data are reported for the 193 patients who had been enrolled for 12 months; life table analysis is reported for all patients who remained enrolled at the study's end as well as for a comparative control group of 623 patients. For the 193 patients for whom 12-month data were available, the number of patients in the low-risk category (HbA(1c) <7%) increased by 51.1%. A total of 97.4% of patients with an HbA(1c) >8% at baseline had a change in treatment regimen. Patients at the highest risk for coronary heart disease (LDL >130 mg/dl) decreased from 25.4% at baseline to 20.2%. Patients with a blood pressure <130/85 mmHg increased from 23.8 to 44.6%. Of these patients, 63.0% had changes in medication. Patients and providers expressed significant increases in satisfaction with the program. CONCLUSIONS: The program was successful in initiating the recommended changes in the diabetic therapeutic regimen, resulting in improved glycemic control, increased monitoring/management of diabetic complications, and greater patient and provider satisfaction. These results should have great significance in the design of future programs in MCOs aimed at improving the care of people with diabetes and other chronic diseases.

Adult↗
PubMed2000

Caregivers' preferences for the treatment of patients with Alzheimer's disease.

OBJECTIVES: To learn caregivers' preferences for the treatment of AD with a disease-slowing therapy, and to identify relationships between these preferences and the characteristics of caregivers and patients. METHODS: A structured interview with 40 caregivers of patients with AD. Preferences were measured for an AD-slowing medicine with the benefits of a gain in survival and a delay to nursing home placement (NHP), and risks of three degrees of severity of GI bleeding. RESULTS: Using a six-point scale ranging from "not at all important" to "extremely important," the median rating of the importance of survival as a treatment benefit was "very important" and of a delay to NHP was "extremely important." Fifty-five percent of the caregivers identified a benefit more important than these two benefits. Qualitative data showed that caregivers' reasons for these preferences featured the importance of patient quality of life, and the preservation of patient cognition and function. Bivariate analyses showed that increasing importance of the benefit of survival was related to higher assessments of the patient's health and quality of life, and lower ratings of the caregiver's experience of burden. In order to slow disease progression by 1 year, 25/38 (66%) of caregivers would accept some risk of death from gastrointestinal bleeding. Regression models showed that risk tolerance was higher among caregivers who were working, adult children caring for early stage patients or from families with an history of dementia. CONCLUSIONS: Caregivers generally are willing to tolerate notable amounts of risk to slow AD progression. Factors that describe the caregiver's experience and perception of the patient and the patient-caregiver relationship influence how they want to treat the disease. This information may be useful for decisions about how to study and prescribe AD treatments.

Adult↗
PubMed2000

Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease.

BACKGROUND: Dementia is a frequent complication of idiopathic parkinsonism or PD, usually occurring later in the protracted course of the illness. The primary site of neuropathologic change in PD is the substantia nigra, but the neuropathologic and molecular basis of dementia in PD is less clear. Although Alzheimer's pathology has been a frequent finding, recent advances in immunostaining of alpha-synuclein have suggested the possible importance of cortical Lewy bodies (CLBs) in the brains of demented patients with PD. METHODS: The brains of 22 demented and 20 nondemented patients with a clinical and neuropathologic diagnosis of PD were evaluated with standard neuropathologic techniques. In addition, CLBs and dystrophic neurites were identified immunohistochemically with antibodies specific for alpha-synuclein and ubiquitin; plaques and tangles were identified by staining with thioflavine S. Associations between dementia status and pathologic markers were tested with logistic regression. RESULTS: CLBs positive for alpha-synuclein are highly sensitive (91%) and specific (90%) neuropathologic markers of dementia in PD and slightly more sensitive than ubiquitin-positive CLBs. They are better indicators of dementia than neurofibrillary tangles, amyloid plaques, or dystrophic neurites. CONCLUSION: CLBs detected by alpha-synuclein antibodies in patients with PD are a more sensitive and specific correlate of dementia than the presence of Alzheimer's pathology, which was present in a minority of the cases in this series.

Adolescent↗
PubMed2000

Therapeutic effects of imipramine are counteracted by its metabolite, desipramine, in patients with generalized anxiety disorder.

Imipramine has been shown to reduce anxiety in patients with generalized anxiety disorder (GAD). However, some properties of imipramine may diminish or counteract its anxiolytic effects. The authors previously found that the greater the reduction in cardiac vagal control after 6 weeks of imipramine treatment, the smaller the improvement in anxiety-related symptoms. The purpose of this study was to determine whether the authors' previous findings were replicable and to gather information on the plasma levels of imipramine, desipramine (the major metabolite of imipramine), and anticholinergic levels. Fourteen patients with GAD were administered imipramine for 6 weeks. Their scores from self-administered and investigator-administered rating scales were obtained before and after the treatment, and the changes in these scores were contrasted with the changes in cardiac vagal tone, along with the absolute plasma levels of imipramine, desipramine, and anticholinergic activity at the end of week 6. The authors observed a greater improvement in symptoms of anxiety in those who showed the smallest decreases in cardiac vagal tone and in those who showed the smallest increases in desipramine and anticholinergic plasma levels. Moreover, strong relationships were observed between desipramine and anticholinergic levels. These results demonstrate that imipramine not only has therapeutic effects, but it may also have properties that result in physiologic states that counteract its therapeutic effects. Future research should investigate the direct anticholinergic effects of desipramine and determine whether there is a parallel between the anticholinergic effects and the clinical outcome of other pharmacologic treatments, including antidepressants with predominantly norepinephrine or serotonin reuptake inhibitory properties.

Adrenergic Uptake Inhibitors↗
PubMed2000

Structural and functional brain integrity of fetal alcohol syndrome in nonretarded cases.

PURPOSE: To determine the structural and functional integrity of the brain in a sample of nonretarded individuals diagnosed with fetal alcohol syndrome. SUBJECTS: The sample consisted of nineteen individuals who met the diagnostic criteria for fetal alcohol syndrome. METHODS: Intellectual function was assessed using the Wechsler Adult Intelligence Scale-Revised. Structural integrity of the brain was assessed using magnetic resonance imaging whereas functional integrity was assessed using positron emission tomography and (18)F-fluorodeoxyglucose. RESULTS: The mean Full Scale IQ was 80. 2 (range: 66-92). Only 1 magnetic resonance imaging was found to be abnormal. This abnormality was found for the subject with the lowest IQ. Decreases in relative regional cerebral metabolic rates were found in 5 brain regions comprising the thalamus and basal ganglia. CONCLUSION: These results when coupled with previous findings suggest a continuum of neuropathology in fetal alcohol syndrome. For cases with relatively mild intellectual deficits, the cause of the deficit is at a micro-level rather than a macro-level.

Adolescent↗