Biomedical subjects
Publications and source records attributed to W J Burke.
This case vignette illustrates dramatic improvement of tardive dyskinesia (TD) in an elderly female with a long history of neuroleptic exposure, following treatment with low-dose risperidone. The TD continued to be in remission at 1-year follow-up. This observation calls for well-designed randomized studies to evaluate the efficacy of risperidone in treating TD.
Explore the source record for details and available documents.
OBJECTIVE: To evaluate prospectively the reliability and validity of the Geriatric Depression Scale administered by telephone (T-GDS) in patients undergoing outpatient comprehensive geriatric assessment. SUBJECTS: A total of 101 geriatric patients were evaluated in a 1-year period at the outpatient Geriatric Assessment Center of the University of Nebraska Medical Center. METHODS: The 30-item GDS was completed by all patients on three occasions: by telephone several days before their assessment, face-to-face during their assessment visit, and several days later, again by phone. During their assessment, all patients were evaluated by one of three geriatric psychiatrists who were blind to all GDS results. The test-retest reliability of the T-GDS was measured by comparing the results of the two phone interviews. The construct validity of the T-GDS was estimated by comparing the results of the initial T-GDS to the GDS obtained during the comprehensive assessment. The criterion validity of the T-GDS was estimated by comparing the results of the T-GDS with the clinical diagnosis of depression assigned by the psychiatrists. RESULTS: The individual items of the initial T-GDS showed substantial concordance with the second T-GDS (kappa range 0.35-0.75, mean = 0.52), and with the assessment GDS (kappa range 0.29-0.75, mean = 0.52). One item showed evidence of bias when comparing the two T-GDSs, and two items when comparing the initial T-GDS to the GDS done during the assessment. The mean number of symptomatic responses was not significantly different for the T-GDS versus assessment administration but did decline slightly when comparing the two T-GDSs. ROC curve analyses showed good agreement between the clinical diagnosis and the T-GDS. CONCLUSION: The GDS appears to maintain its reliability and validity when administered via telephone and thus may be useful for a variety of epidemiological and clinical purposes.
Patients diagnosed with major depressive disorder (MDD) and enrolled in an open-label safety surveillance study of a sustained release formulation of bupropion hydrochloride (100 to 300 mg/day) were evaluated with the Hamilton Rating Scale for Depression (HAM-D) immediately before and 6 to 12 weeks after the initiation of drug treatment. Auditory event-related potentials (ERPs) recorded under a stimulus intensity modulation paradigm were also obtained at these times. Patients were classified as responders and nonresponders based on post-treatment HAM-D scores, with responders having HAM-D scores less than 10 and nonresponders having scores greater than 10. Consistent with our previous findings, responders exhibited significantly larger positive slope coefficients for P2 ERP component amplitudes as a function of auditory stimulus intensity obtained at baseline and were not affected by bupropion treatment. Thus, these results further support our previous finding that ERP amplitude/intensity functions measured under a stimulus intensity modulation paradigm provide information about the likelihood of a positive therapeutic response to antidepressant pharmacotherapy in patients with MDD and extends these results to bupropion, a pharmacologically atypical antidepressant agent.
The C-1 region in the rostral ventral lateral medulla contains mainly epinephrine (Epi) neurons. These neurons are the tonic vasomotor center of the brain. We previously demonstrated changes in the enzymatic activity of phenylethanolamine N-methyltransferase (PNMT) in axon terminals and cell bodies of Epi neurons from the medulla of Alzheimer's disease (AD) brains. In this study, we investigated the perikarya of C-1 neurons for the morphometric, immunohistochemical and histochemical changes that are seen in severely affected regions of Alzheimer brain. The mean areas and size distributions of C-1 neurons from 6 AD and 6 neurologically normal patients were compared using the Wilcoxon rank sum test and Kolmogorov-Smirnov z tests respectively. Additional brain sections from the C-1 region of AD and control individuals were stained with cresyl violet or immunostained with antibodies to the lysosomal hydrolase cathepsin D, Tau-2, Alz-50 and beta-amyloid protein. The average area of C-1 neurons in AD brains was decreased 18.3% (P < 0.001) compared to the areas of the same cell population in age-matched control brains. A shift toward smaller sized C-1 neurons was seen in the AD cases. Nissl stain demonstrated a central chromatolytic appearance in 3.7% of AD neurons sampled. No beta-amyloid deposits were detected histologically or immunocytochemically in the C-1 region of AD brains. Both Tau-2 and Alz-50 immunoreactivity was observed in occasional (1%) C-1 neurons from AD brains but not in controls. A small proportion (30%) of the C-1 neurons showing atrophy displayed increased cathepsin D immunoreactivity.(ABSTRACT TRUNCATED AT 250 WORDS)
Elevated levels of intraneuronal calcium may contribute to neuronal death in both Alzheimer's disease and stroke. In part, this neuronal death may be due to calcium-induced disruption of microtubules and inhibition of axonal transport. Taxol stabilizes microtubules to disaggregation. To determine whether taxol could protect against calcium-mediated neuron cell death, a test system was established using a nerve growth factor-differentiated rat pheochromocytoma cell line (PC12 cells). PC12 cells were cultured with nerve growth factor to induce a neuronal phenotype. After 15 days, the cells were exposed to taxol, the calcium ionophore, A23187, or taxol plus ionophore for up to 24 h. Taxol alone reduced cell survival in a concentration dependent manner. At a concentration of 50 nM survival was reduced to between 63% and 84% of control after 4 h of exposure. The ionophore (1 microM) variably reduced cell survival to between 10 and 55% at 4h. However, when taxol was added to the ionophore the cell survival was significantly increased by 1.5 to 4-fold. The protective effect of taxol lasted up to 24h. We conclude that taxol has a protective effect on calcium-mediated neurotoxicity. Drugs targeting underlying cellular mechanisms involved in calcium-mediated neuronal death may lead to successful therapy for Alzheimer's disease and stroke.
Brain neurons which regulate blood pressure (BP), including the C-1 tonic vasomotor neurons, degenerate in Alzheimer's disease (AD). This study determines whether BP is decreased in AD. We reviewed records of three autopsy proven AD patients. Medical causes for decreased BP were investigated. Yearly averages for systolic (SBP), diastolic (DBP), mean arterial (AP) blood pressure and pulse pressure (PP) were calculated. BP in the year of diagnosis was compared to the sum of all BP in subsequent years. In addition, each yearly measurement through the course of AD was compared to its counterpart in the year of diagnosis. Three BP measurements were significantly decreased by from 6.9% to 15.9% in all patients when BP in the year of diagnosis was compared to the sum of each pressure in subsequent years. Sustained BP declines started in the third to fourth year after diagnosis of AD and continued for up to 9 years. The PP was decreased by 19.9% in one patient. There was a strong correlation between the number of C-1 neurons in these cases and their AP and SBP in the years after diagnosis. Hypothalamic phenylethanolamine N-methyltransferase activity was decreased by 63% in AD compared to control cases. Neurofibrillary tangles were found in the paraventricular nucleus of the hypothalamus in an AD case. We postulate that BP is altered in AD as neurons which regulate it degenerate.
Epidemiologic necropsy provides an accurate measure of the occurrence rates of diseases. To determine the occurrence of cancer in Alzheimer patients as well as in non-Alzheimer elderly controls, we examined autopsy reports of 575 control and 71 Alzheimer cases aged 50-100 years for histologic evidence of cancer. We compared expected rates of cancers calculated from the National Cancer Institute's Surveillance, Epidemiology and End Result (SEER) Program data to rates observed at autopsy using a chi-squared test. To determine whether there was an association between the occurrence of cancer and Alzheimer disease, we compared rates for all cancer and three specific cancers in Alzheimer and control patients using an odds ratio test. We found from fourfold to 98-fold more cancer in Alzheimer patients and controls than that expected from SEER data. There was no statistical difference in the autopsy incidence of total, lung, or prostate cancer between Alzheimer patients and controls. However, the occurrence of pancreatic cancer was 6.7-fold higher in Alzheimer patients than in control subjects. Controlling for multiple comparisons, the odds ratio for pancreatic cancer in Alzheimer's disease was significantly higher than in controls (p < 0.001). Our results indicate that cancer occurs more frequently than expected in both Alzheimer patients and control subjects. In addition, there may be an association between the occurrence of certain cancers and Alzheimer's disease.
Explore the source record for details and available documents.
Since opioids can influence the release of acetylcholine, substance P and a number of other neurotransmitters that have been implicated in the pathogenesis of Alzheimer's disease (AD), it is of interest to assess opioid receptor levels in AD. We have examined mu, delta and kappa opioid receptor binding parameters, binding sensitivity to a GTP analog and distribution in amygdala, frontal cortex and putamen of AD brain. Control brains were matched according to age, sex, post-mortem interval and storage time. Kd values and GTP analog binding sensitivity did not differ in AD and control brains. Bmax values for mu ([3H]DAMGE) sites also appeared unaffected by in vitro binding assays. In contrast, kappa ([3H]U69593) and delta ([3H]DSLET) opioid receptor levels, were significantly changed. In AD amygdala kappa Bmax values increased from control levels of 123 +/- 12 to 168 +/- 13 fmol/mg protein, whereas densities of kappa and delta sites were decreased from 94 +/- 8 to 48 +/- 8 and 102 +/- 3.6 to 69 +/- 8.5 fmol/mg protein, respectively, in putamen. Autoradiography revealed corresponding differences in the distribution of kappa opioid receptors. The findings indicate that the kappa binding site, which is quantitatively the major opioid receptor class in human brain, undergoes marked changes in AD amygdala and putamen.
Explore the source record for details and available documents.
OBJECTIVE: To examine the short-term cognitive and behavioral effects of L-deprenyl in persons with mild dementia of the Alzheimer type (DAT) over a 2-month period. DESIGN: A 15-month randomized, double-blind, placebo-controlled trial using a parallel-group design. This report deals with the first 2 months of the trial. PARTICIPANTS: 39 subjects with mild DAT (CDR 1) selected using NINCDS-ADRDA criteria. MEASURES: A battery of neuropsychological tests and clinical rating scales. RESULTS: The placebo and L-deprenyl subjects were similar at baseline on the clinical and neuropsychological tests. There was no evidence of a L-deprenyl effect on any clinical or neuropsychological measures after 2 months. CONCLUSION: L-deprenyl did not have a measurable impact on behavior or cognitive function over a 2-month period in this group of subjects with mild DAT.
OBJECTIVE: To examine the cognitive and behavioral effects of L-deprenyl in persons with mild dementia of the Alzheimer type (DAT) over a 15-month period. DESIGN: A 15-month randomized, double-blind, placebo-controlled trial using a parallel-group design. PARTICIPANTS: 39 subjects with mild DAT (CDR 1) selected using NINCDS-ADRDA criteria. OUTCOME MEASURES: A battery of neuropsychological tests and clinical rating scales. RESULTS: The placebo and L-deprenyl subjects were similar at baseline on the clinical and neuropsychological tests. The total score on the Brief Psychiatric Rating Scale (BPRS) was significantly less after 15 months in subjects taking L-deprenyl. The only individual item of the BPRS which differed between groups was disorientation. There was no evidence of a L-deprenyl effect on any other clinical or neuropsychological measure after 2, 8, or 15 months. CONCLUSION: L-deprenyl did appear to have a slight effect on a single measure of psychopathology, the BPRS. It did not have a measurable impact on any other measure of behavior or cognitive function over a 15-month period in this group of subjects with mild DAT and did not appear to slow the progression of the disease.
Explore the source record for details and available documents.
OBJECTIVE: To assess the construct validity of a telephone-administered version of the Mini-Mental State Examination (MMSE). DESIGN: Validity testing by comparing a telephone version of the MMSE administered first to a face-to-face evaluation done several days later. SETTING: Outpatient geriatric assessment center. SUBJECTS: 100 of 175 consecutive referrals. MAIN OUTCOME MEASURES: MMSE and a brief neuropsychological screening test (BNPS) face-to-face and a telephone version of the MMSE as part of the Adult Lifestyles and Function Interview (ALFI-MMSE). RESULTS: Test scores of the two MMSE versions correlated strongly for all subjects (Pearson's r = 0.85, P = 0.001) and remained significant for the cognitively intact (P = 0.02) and questionably (P = 0.002), mildly (P = 0.0001), and moderately (P = 0.003) demented. Comparison of the two versions' equivalent 22 items revealed no significant difference for scores of all subjects (P = 0.07) but with a trend toward higher scores in the original version. Diminished hearing, reported either by the subject (P = 0.003) or by the collateral source (P = 0.02) was associated with lower scores on the telephone version. Five individual test items were biased by the route of test administration. Sensitivity and specificity relative to the BNPS were 67% and 100% for the ALFI-MMSE and 68% and 100% for the MMSE, respectively. CONCLUSION: The scores on the ALFI-MMSE correlated strongly with the scores of the original version given face-to-face in subjects undergoing geriatric assessment. The results indicate that the ALFI-MMSE could be a useful and economical tool to screen for cognitive impairment.
OBJECTIVE: To prospectively evaluate the Geriatric Depression Scale (GDS) in cognitively intact and impaired patients undergoing outpatient geriatric assessment. SUBJECTS: One hundred ninety-four geriatric patients evaluated in a 1-year period. SETTING: The outpatient Geriatric Assessment Center of the University of Nebraska Medical Center. MEASUREMENTS: The 30-item GDS was completed by all patients. The patients were then evaluated by one of three geriatric psychiatrists who were blind to the GDS results. The prospective clinical diagnosis of major depression was compared to the GDS results. Patients were categorized as cognitively impaired or intact on the basis of the Mini-Mental State Examination. Data were analyzed using ROC curves. An optimal cutoff was identified which was the total score on the GDS with the highest combined sensitivity and specificity. RESULTS: ROC curve analyses showed good agreement between the clinical diagnosis and the GDS in both cognitively intact and impaired subjects. Cognitively intact, euthymic patients reported a mean of 8.4 symptoms, while cognitively impaired, euthymic patients, reported a mean of 8.7. Cognitively intact, depressed patients reported a mean of 14.7 symptoms, while cognitively impaired, depressed patients reported a mean of 15.0. CONCLUSIONS: This study provides further evidence that the GDS is as accurate a screening test for depression in cognitively impaired as in intact patients.
Choline acetyltransferase (Acetyl-CoA: choline O-acetyltransferase: EC 2.3.1.6) (ChAT) enzyme activity and neuron density were measured in the locus ceruleus (LC) of autopsied brains of neurologically normal individuals and patients who had Alzheimer's disease. Neuron density in the LC of individuals with Alzheimer's was significantly reduced to approximately 50% of normal values. ChAT activity was also reduced by about 50%. Furthermore, the number of pigmented neurons in the LC was highly correlated with presynaptic ChAT activity. These findings were specific for the LC, since deficits in ChAT and neuron density were not found in two adrenergic brainstem nuclei (C1 and C2). We measured mitogen activity in LC extracts in order to determine whether loss of cholinergic afferents to the LC, as evidenced by loss of ChAT, was related to putative trophic factors. Mitogen activity was significantly reduced (50%) in the Alzheimer's group as compared to normals. Mitogen activity was significantly correlated with ChAT activity and the density of neurons in the LC. The loss of cholinergic nerve terminals in the LC in Alzheimer's disease may be functionally significant, since acetylcholine has important effects on LC physiology. The highly significant relationships between ChAT, neuron density and mitogen activity has important implications for our understanding of mechanisms of neurodegeneration in Alzheimer's disease.
The method of polymerase chain reaction was used to investigate the pre- and postmortem factors which affect the stability of specific mRNAs in the C1 region of human autopsy brain. Eight premortem and 4 postmortem factors were correlated to levels of phenylethanolamine N-methyltransferase (PNMT), three splice forms of amyloid precursor protein (APP) and actin mRNAs in 10 control brains using Pearson's correlation coefficient. Significant negative correlations were found between hypoxia and PNMT mRNA, and between postmortem and storage intervals and APP751 and beta-actin mRNAs. A positive correlation was found between death-refrigeration interval and total APP and APP695 mRNAs. There was also a positive correlation between seizure activity and APP770 mRNA. The results indicate that a variety of pre- and postmortem factors can affect mRNA levels. The possible effect of pre- and postmortem factors on specific mRNA levels should be investigated prior to comparing mRNA levels in different disease states.