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Biomedical subjects

G W Small

Publications and source records attributed to G W Small.

At least 19 recordsLinked to original sources
PubMed1997

D2 dopamine receptor A1 allele in Alzheimer disease and aging.

BACKGROUND: The apolipoprotein E4 (APOE*4) allele is a major risk factor for the common forms of late-onset Alzheimer disease (AD), but does not account for all the genetic variation in late-onset AD; hence, other genetic markers must be examined. The D2 dopamine receptor (DRD2) A1 allele is associated with abnormal brain function and decreased DRD2s. These receptors are decreased in hippocampus and amygdala in AD, and allele frequencies may vary with age. OBJECTIVE: To study APOE and DRD2 genotypes in patients with AD and cognitively intact controls of varying ages. DESIGN: The DRD2 and APOE genotypes were examined in 832 unrelated white subjects, including 554 patients with AD (486 sporadic; 68 familial) and 278 controls. Logistic regressions tested A1 allele effects on disease status and age, and DRD2 linkage with AD was investigated in 60 families with late-onset AD. SETTING: University medical centers. SUBJECTS: Patients (mean +/- SD age, 74.6 +/- 8.1 years; range, 52-98 years) had probable AD, according to standard consensus diagnostic criteria; controls (mean +/- SD age, 69.2 +/- 8.6 years; range, 50-93 years) were cognitively intact. MAIN OUTCOME MEASURES: Disease status, age, and DRD2 linkage with AD. RESULTS: No association between the DRD2 and APOE alleles was found, and the presence of the A1 allele did not increase the risk for AD. There was also no evidence of linkage between DRD2 and AD. Age analyses, including both patients and controls, indicated a decrease in A1 allele frequency with age. CONCLUSIONS: The A1 allele does not contribute to AD risk, alone or in combination with the APOE*4 allele. The DRD2 A1 allele frequencies decrease with age in both patients and controls. Thus, studies of DRD2 disease association need to control for age.

Aged↗
PubMed1997

No association or linkage between an intronic polymorphism of presenilin-1 and sporadic or late-onset familial Alzheimer disease.

Recent reports have shown an association between an intronic polymorphism of the presenilin-1 (PSEN1) gene and late-onset (age at onset > 65) familial and sporadic (no family history) Alzheimer disease (AD). The reported association was independent of the effect of the only previously identified gene associated with late-onset AD, APOE. Blood samples were obtained from members of 122 multiplex AD families, 42 unrelated cases of AD with positive family histories of dementia, 456 sporadic cases of AD, and 317 controls of similar ages at examination to the cases. These samples were genotyped for an intronic polymorphism of the PSEN1 gene, located 3' to exon 8, and the data analyzed for evidence of association or linkage. The samples were also genotyped for APOE and the data analyzed to see if the association or linkage changed when controlling for APOE genotype. There was no statistically significant increase (at alpha = .01) in allele 1 (199 bp) or genotype 1/1 in the sporadic AD cases, or in a random sample of one affected from each multiplex family, compared to controls. When examining the effect of the PSEN1 polymorphism while controlling for APOE genotype, APOE genotype was strongly associated with AD, but the PSEN1 polymorphism genotype was not. Model-trait dependent (lod score) and independent (Sim1BD) methods detected no evidence of linkage between PSEN1 and AD. In this independent dataset, the previously reported association between the intronic PSEN1 polymorphism and AD cannot be confirmed, and the conclusion that PSEN1 is a major susceptibility gene for late-onset AD is not supported.

Age of Onset↗
PubMed1997

Mnemonics usage and cognitive decline in age-associated memory impairment.

To determine predictors of cognitive deterioration, the authors performed baseline and 1- to 5-year follow-up (mean +/- SD = 2.5 +/- 1.2 years) neuropsychological assessments on 36 persons (mean age +/- SD = 62.1 +/- 8.0; range = 50 to 81 years) with age-associated memory impairment. Subjects were recruited from a larger group of volunteers, had minimal medical comorbidity, and 25 of them had a family history of Alzheimer's disease. Baseline age and a subjective memory measure indicating reported frequency of mnemonics usage were significant decline predictors. Subjects reporting more frequent mnemonics use at baseline were more likely to show objective cognitive decline at follow-up. Baseline full-scale IQ, educational level, and family history of Alzheimer's disease failed to predict decline. These findings suggest that although age is the strongest decline predictor in some people with age-associated memory impairment, self-perception of memory function may also predict subsequent cognitive loss.

Abbreviations as Topic↗
PubMed1997

Estrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. Fluoxetine Collaborative Study Group.

The estrogen decrease of the postmenopausal state may be a factor in both the pathogenesis of late-life depression and in therapeutic response. Studies of nondepressed women over 60 given estrogen replacement therapy (ERT) suggest improvement in mood. The authors compared clinical response of elderly depressed women outpatients entering a 6-week, randomized, placebo-controlled, double-blind, multicenter trial of fluoxetine (20 mg/day); 72 patients received ERT, and 286 did not. There was a significant interaction between ERT status and treatment effect (P = 0.015). Patients on ERT who received fluoxetine had substantially greater mean Ham-D percentage improvement than patients on ERT who received placebo (40.1% vs. 17.0%, respectively); fluoxetine-treated patients not on ERT did not show benefit significantly greater than placebo-treated patients not on ERT. ERT use may augment fluoxetine response in elderly depressed outpatients and should be considered as a factor in clinical trials in elderly women.

Affect↗
PubMed1997

Recognizing and treating anxiety in the elderly.

Anxiety in the elderly is often unrecognized and inadequately treated. Several factors complicate recognition and treatment, including concomitant medical illness, overlap with cognitive disorders, cohort effects, ageism, and cormorbid depression. Although available data from controlled clinical trials are limited for anxiety patients in the geriatric age group, data from young adult studies and clinical experience indicate that pharmacologic treatments are safe and effective for anxious elderly patients. Age-related physiologic changes warrant modifications in dosing, including initial low doses increased in gradual increments. Education and psychotherapy are often recommended whether or not pharmacologic treatment is indicated.

Age Factors↗
PubMed1996

No association between alpha 1-antichymotrypsin and familial Alzheimer's disease.

Alzheimer's disease (AD) is the most common mid to late age-of-onset neurodegenerative disorder. AD has a strong and complex genetic etiology, and multiple genes, acting independently and/or interacting, likely affect the risk of developing AD. Several genes involved with AD already have been described, but only the APOE gene on chromosome 19q has been shown to affect the risk of the most common form of AD, occurring with onset over the age of 65. Because a substantial portion of late-onset AD is not explained by APOE, other genes affecting late-onset AD likely occur. These could act either independently or perhaps interact with APOE. alpha 1-Antichymotrypsin (ACT) is a major component of the amyloid plaques found in the brains of AD patients and may play a role in the pathophysiology of AD. It has been proposed that a specific polymorphism within the ACT gene interacts with APOE to increase the risk of developing AD. Our results do not confirm this finding.

Adult↗
PubMed1996

Early detection of Alzheimer's disease by combining apolipoprotein E and neuroimaging.

New treatments for Alzheimer's disease (AD) are more likely to slow or halt disease progression rather than to reverse existing neuronal damage. Identifying persons with mild cognitive complaints who are at risk for AD will allow investigators to apply anti-dementia treatments before extensive brain damage develops. The discovery of the apolipoprotein E epsilon 4 allele (APOE epsilon 4) as a major risk factor for AD offers promise of assisting in early detection and prediction of Alzheimer's disease, particularly when genetic assessments are combined with other biomarkers such as neuroimaging. Studies of relatives at risk for familial AD using neuroimaging (positron emission tomography [PET]) and genetic assessments of APOE suggest that at-risk relatives with APOE epsilon 4 have lower parietal metabolism than those without APOE epsilon 4. Additional techniques that might increase sensitivity and specificity include longitudinal assessment of clinical and brain functional change, pharmacological challenges of short-acting anticholinergic agents, and memory activation paradigms during functional scanning. Such strategies should eventually assist in early detection of AD and in vivo therapeutic monitoring of brain function during experimental anti-dementia treatment trials.

Adult↗
PubMed1996

Genetic algorithm-based method for selecting wavelengths and model size for use with partial least-squares regression: application to near-infrared spectroscopy.

Genetic algorithms (GAs) are used to implement an automated wavelength selection procedure for use in building multivariate calibration models based on partial least-squares regression. The method also allows the number of latent variables used in constructing the calibration models to be optimized along with the selection of the wavelengths. The data used to test this methodology are derived from the determination of aqueous organic species by near-infrared spectroscopy. The three data sets employed focus on the determination of (1) methyl isobutyl ketone in water over the range of 1-160 ppm, (2) physiological levels of glucose in a phosphate buffer matrix containing bovine serum albumin and triacetin, and (3) glucose in a human serum matrix. These data sets feature analyte signals near the limit of detection and the presence of significant spectral interferences. Studies are performed to characterize the signal and noise characteristics of the spectral data, and optimal configurations for the GA are found for each data set through experimental design techniques. Despite the complexity of the spectral data, the GA procedure is found to perform well, leading to calibration models that significantly outperform those based on full spectrum analyses. In addition, a significant reduction in the number of spectral points required to build the models is realized.

Algorithms↗
PubMed1996

Genetic algorithm-based protocol for coupling digital filtering and partial least-squares regression: application to the near-infrared analysis of glucose in biological matrices.

A multivariate calibration procedure is described that is based on the use of a genetic algorithm (GA) to guide the coupling of bandpass digital filtering and partial least-squares (PLS) regression. The measurement of glucose in three different biological matrices with near-infrared spectroscopy is employed to develop this protocol. The GA is employed to optimize the position and width of the bandpass digital filter, the spectral range for PLS regression, and the number of PLS factors used in building the calibration model. The optimization of these variables is difficult because the values of the variables employ different units, resulting in a tendency for local optima to occur on the response surface of the optimization. Two issues are found to be critical to the success of the optimization: the configuration of the GA and the development of an appropriate fitness function. An integer representation for the GA is employed to overcome the difficulty in optimizing variables that are dissimilar, and the optimal GA configuration is found through experimental design methods. Three fitness function calculations are compared for their ability to lead the GA to better calibration models. A fitness function based on the combination of the mean-squared error in the calibration set data, the mean-squared error in the monitoring set data, and the number of PLS factors raised to a weighting factor is found to perform best. Multiple random drawings of the calibration and monitoring sets are also found to improve the optimization performance. Using this fitness function and three random drawings of the calibration and monitoring sets, the GA found calibration models that required fewer PLS factors yet had similar or better prediction abilities compared to calibration models found through an optimization protocol based on a grid search method.

Algorithms↗
PubMed1996

No association between very low density lipoprotein receptor (VLDL-R) and Alzheimer disease in American Caucasians.

The very low density lipoprotein receptor gene (VLDL-R) is a receptor for apolipoprotein-epsilon (APOE)-containing lipoproteins, and thus has been suggested as a possible risk factor for Alzheimer disease (AD). Recently, Okuizumi et al. [Nature Genet, II (1995) 207-209] reported an association between the 96 bp allele at the VLDL-R locus and AD in a Japanese population. The association resulted in a two-fold increase of risk that decreased with increasing age. We have examined this association in 316 Caucasian sporadic AD patients, comparing their findings to 160 Caucasian AD spouse controls. We also investigated 53 late-onset Caucasian AD families for association and linkage. Our data failed to confirm linkage and/or association to the VLDL-R locus. Stratification by age at onset or APOE genotype also failed to show significant results.

Adult↗
PubMed1996

No genetic effect of alpha1-antichymotrypsin in Alzheimer disease.

Alzheimer disease (AD) is the most common neurodegenerative disorder for individuals over the age of 40. AD has a complex etiology, and it is likely that multiple genes, acting independently and/or interacting, affect the risk of developing AD. Several genes involved with AD have been described already, but only the APOE gene on chromosome 19q has been shown to affect the risk of the common late onset form of AD. alpha1-Antichymotrypsin (AACT) is a major component of the amyloid plaques found in the brains of AD patients, and an allele in its gene has been proposed to increase the risk of developing AD when also associated with the APOE-4 allele. We have examined the role of this AACT polymorphism in a large set of families and sporadic cases, and do not see any effect, either alone or in combination with the APOE-4 allele.

Alzheimer Disease↗
PubMed1996

Near-infrared spectroscopic measurement of physiological glucose levels in variable matrices of protein and triglycerides.

Selective calibration models are generated for glucose over the 1-20 nM concentration range by use of partial least-squares regression analysis of near-infrared spectra from 5000 to 4000 cm-1. Two spectral data sets are used to simulate triglyceride and protein variations in clinical samples. Triacetin is used in one data set to simulate variations in triglyceride levels, and bovine serum albumin (BSA) is used in the second data set to simulate variations in blood protein levels. Although these matrix components possess strong absorption bands that overlap and overshadow the absorption bands of glucose, successful calibration models can be generated with no evidence of prediction bias caused by the different levels of the matrix components. Furthermore, the benefits of using digital Fourier filtering as a preprocessing step are evaluated in terms of calibration performance. The resulting calibration models provide standard errors of prediction of 0.5 and 0.2 mM in triacetin and BSA matrices, respectively. Accurate glucose predictions are demonstrated from spectra that correspond to protein concentrations not present in the calibration data set. Lastly, digital Fourier filtering alone is shown to have only limited ability to isolate glucose signals from those of BSA and triacetin due to similarities in the widths of the absorption bands of the three species.

Animals↗
PubMed1996

Impact of physical illness on quality of life and antidepressant response in geriatric major depression. Fluoxetine Collaborative Study Group.

OBJECTIVE: Because physical illness may influence quality of life, we assessed its impact on functional status and treatment outcome in older depressed patients who participated in a clinical trial, which showed a significantly higher remission rate for fluoxetine over placebo (31.6% vs 18.6%, P < .001). DESIGN: Six-week, randomized, double-blind, placebo-controlled trial of fluoxetine, 20 mg daily. SETTING: Multiple clinical sites, both university and private. PARTICIPANTS: Outpatients (N = 671) were > or = 60 years (mean +/- SD = 67.7 +/- 5.7), met DSM-III-R criteria for unipolar major depression and had baseline scores > or = 16 on the Hamilton Depression Rating Scale. MEASUREMENTS: The 36-item short-form health survey (SF-36) was used to measure baseline and posttreatment functional health and well-being. Physical illness was rated by number of current chronic or historical illnesses. Change from baseline to endpoint in the Hamilton Depression Rating Scale total score was used to measure depression outcome. MAIN RESULTS: Most patients reported physical illness: 83% had one or more chronic illness, and 89% had one or more historical illness. Greater numbers of baseline chronic illness indicated worse physical functioning, general health perceptions, and vitality and greater bodily pain and role limitation from physical problems. Historical physical illness was associated with worse physical functioning, vitality, general health perceptions, social functioning, and mental health. Although the number of chronic illnesses did not influence treatment response, historical physical illness was associated with greater fluoxetine response and lower placebo response. CONCLUSIONS: These findings suggest that both current and previous physical illness are associated with lower quality of life in geriatric depression and that depressed older patients with chronic physical illness respond to antidepressants as well as those without such illness. Recovery from previous physical illness should be explored as a potential predictor of antidepressant treatment outcome.

Aged↗
PubMed1996

Neuroimaging and genetic assessment for early diagnosis of Alzheimer's disease.

Identifying persons with mild cognitive complaints who are at risk for Alzheimer's disease (AD) will enable the start of antidementia treatments before extensive brain damage develops. Recent research developments link the apolipoprotein E-4 (APOE-4) allele to late-onset familial and late-onset sporadic AD. Studies of relatives at risk for familial AD using brain imaging (positron emission tomography [PET]) and genetic assessments suggest that relatives with the APOE-4 allele have lower parietal metabolism than those without this allele. Approaches that might increase sensitivity and specificity include, among others, pharmacologic challenges of short-acting anticholinergic agents and memory activation during functional scanning. Such strategies should eventually assist in early detection of AD and in vivo therapeutic monitoring of brain function during experimental antidementia treatment trials.

Age of Onset↗
PubMed1995

Quantitative analysis of bandpass-filtered Fourier transform infrared interferograms.

The feasibility of performing quantitative analysis with short segments of bandpass-filtered Fourier transform infrared (FT-IR) interferograms is demonstrated. The protocol developed in this work addresses four limitations that hinder the use of FT-IR spectroscopy in nonlaboratory applications: (1) the need for a rugged, low-cost, and reliable spectrometer, (2) the lack of representative background spectra for use in acquiring absorbance spectra of the target analyte, (3) the presence of overlapping spectral bands that interfere with the analyte determination, and (4) the difficulty in obtaining useful information from data collected near the limit of detection. In this work, spectral information pertaining to a specific analyte band of interest is isolated directly from a short interferogram segment by the application of narrow-bandpass digital filters. When processed in this way, the filtered interferogram segments contain compound-specific information that can be utilized for quantitative analysis. Successful use of a univariate calibration procedure with filtered interferogram data of benzene and nitrobenzene of varying concentrations is demonstrated. Calibrations based on filtered interferogram segment magnitudes vs concentration yield models with values of R2 in excess of 99%. These results are obtained without the use of a separate background or reference interferogram. This interferogram-based analysis is shown to perform analogously to a conventional spectral-based analysis, with the interferogram method being more efficient in terms of data collection and computational requirements.

Benzene Derivatives↗
PubMed1995

Clinical response predictors in a double-blind, placebo-controlled trial of fluoxetine for geriatric major depression. Fluoxetine Collaborative Study Group.

BACKGROUND: We attempted to determine baseline characteristics predicting response in a 6-week, double-blind, geriatric depression trial, which showed a significantly higher remission rate for fluoxetine (20 mg daily) than for placebo (31.6% vs. 18.6%, p < .001). METHODS: Outpatients (N = 671) were 60 years or older (mean +/- SD = 67.7 +/- 5.7), met Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev., American Psychiatric Association, 1987) criteria for unipolar major depression, had baseline scores on the 17-item Hamilton Depression Rating Scale (HAMD17) of 16 or more, and were randomized after a 1-week placebo lead-in. Potential baseline predictors of percentage change in last-visit-carried-forward HAMD21 total scores were entered into a stepwise regression model. The sample was randomly divided into two groups (development and validation data sets) so that potential predictors could be confirmed in a second analysis. RESULTS: Of the 266 variables considered for their prognostic ability, 13 were found to be significant predictors using the development data set, including (a) presence of somatic complaints, absence of agitation, and presence of previous accidental injury for fluoxetine response; and (b) reported feelings of emptiness, absence of somatic complaints, and absence of early insomnia for placebo response. The second analysis using the validation data set failed to confirm statistical significance of predictors identified in the development data set. CONCLUSIONS: Although potentially useful baseline characteristics were initially identified as response predictors, conservative statistical methods failed to confirm any significant predictors of differential responses between fluoxetine and placebo in this double-blind, placebo-controlled trial. These results suggest that response predictor analyses require confirmation before conclusions can be generalized.

Aged↗
PubMed1995

Evaluation of accuracy and reproducibility of E test for susceptibility testing of Streptococcus pneumoniae to penicillin, cefotaxime, and ceftriaxone.

We evaluated the reproducibility with which technologists perform and interpret the E test (AB Biodisk, North America, Inc., Piscataway, N.J.) for determining the susceptibility of Streptococcus pneumoniae to penicillin, cefotaxime, and ceftriaxone. Four technologists prepared E test assays to test 124 isolates of S. pneumoniae. Each technologist then interpreted the results of the E test blinded to the interpretation of the other technologists. In addition, E test results were compared with the reference method of broth microdilution. Intraobserver and interobserver agreement were assessed by use of the kappa statistic. Interpretation of the E test and broth microdilution results showed substantial to excellent agreement, with kappa values ranging from 0.878 to 0.987. Compared with broth microdilution, no very major errors and only four major errors were made with the E test. Most minor errors with penicillin and ceftriaxone occurred for isolates with intermediate or high-level resistance, whereas for cefotaxime the minor errors were more evenly distributed between susceptible and intermediate resistance and between intermediate and high-level resistance. These results indicate that there is good agreement between technologists for the interpretation of the E test when testing the susceptibility of S. pneumoniae to penicillin, cefotaxime, and ceftriaxone and that the results of the E test agree with those of broth microdilution.

Cefotaxime↗