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Biomedical subjects

G W Small

Publications and source records attributed to G W Small.

At least 37 records · Page 2Linked to original sources
PubMed2001

Estrogen replacement therapy and antidepressant response to sertraline in older depressed women.

The influence of the use of estrogen replacement therapy (ERT) on the antidepressant response to sertraline of 127 women over 60 years old was evaluated with data from two multicenter trials. At endpoint, sertraline-treated women taking ERT had significantly greater global improvement and quality of life than those not receiving ERT. Modest improvements were also observed in anxiety symptoms and cognitive functioning. The results provide preliminary evidence that ERT use (without progesterone) in older depressed women may augment the antidepressant response to sertraline in terms of quality of life and general improvement.

Aged↗
PubMed2000

Patterns of brain activation in people at risk for Alzheimer's disease.

BACKGROUND: The epsilon4 allele of the apolipoprotein E gene (APOE) is the chief known genetic risk factor for Alzheimer's disease, the most common cause of dementia late in life. To determine the relation between brain responses to tasks requiring memory and the genetic risk of Alzheimer's disease, we performed APOE genotyping and functional magnetic resonance imaging (MRI) of the brain in older persons with intact cognition. METHODS: We studied 30 subjects (age, 47 to 82 years) who were neurologically normal, of whom 16 were carriers of the APOE epsilon4 allele and 14 were homozygous for the APOE epsilon3 allele. The mean age and level of education were similar in the two groups. Patterns of brain activation during functional MRI scanning were determined while subjects memorized and recalled unrelated pairs of words and while subjects rested between such periods. Memory was reassessed in 14 subjects two years later. RESULTS: Both the magnitude and the extent of brain activation during memory-activation tasks in regions affected by Alzheimer's disease, including the left hippocampal, parietal, and prefrontal regions, were greater among the carriers of the APOE epsilon4 allele than among the carriers of the APOE epsilon3 allele. During periods of recall, the carriers of the APOE epsilon4 allele had a greater average increase in signal intensity in the hippocampal region (1.03 percent vs. 0.62 percent, P<0.001) and a greater mean (+/-SD) number of activated regions throughout the brain (15.9+/-6.2 vs. 9.4+/-5.5, P=0.005) than did carriers of the APOE epsilon3 allele. Longitudinal assessment after two years indicated that the degree of base-line brain activation correlated with degree of decline in memory. CONCLUSIONS: Patterns of brain activation during tasks requiring memory differ depending on the genetic risk of Alzheimer's disease and may predict a subsequent decline in memory.

Aged↗
PubMed2000

Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease.

The major known genetic risk for Alzheimer's disease (AD), apolipoprotein E-4 (APOE-4), is associated with lowered parietal, temporal, and posterior cingulate cerebral glucose metabolism in patients with a clinical diagnosis of AD. To determine cognitive and metabolic decline patterns according to genetic risk, we investigated cerebral metabolic rates by using positron emission tomography in middle-aged and older nondemented persons with normal memory performance. A single copy of the APOE-4 allele was associated with lowered inferior parietal, lateral temporal, and posterior cingulate metabolism, which predicted cognitive decline after 2 years of longitudinal follow-up. For the 20 nondemented subjects followed longitudinally, memory performance scores did not decline significantly, but cortical metabolic rates did. In APOE-4 carriers, a 4% left posterior cingulate metabolic decline was observed, and inferior parietal and lateral temporal regions demonstrated the greatest magnitude (5%) of metabolic decline after 2 years. These results indicate that the combination of cerebral metabolic rates and genetic risk factors provides a means for preclinical AD detection that will assist in response monitoring during experimental treatments.

Aged↗
PubMed2000

Identification of novel genes in late-onset Alzheimer's disease.

Four genes affecting Alzheimer's Disease (AD)(AP, PS1, PS2, and APOE) have been identified and a fifth potential gene localized to chromosome 12. Collectively, these genes explain at most half of the genetic effect in AD. Understanding the genetics of AD is critical to developing new treatments. The quest to find the remaining AD genes led us to undertake a large genomic screen using over 466 families (730 affected sibpairs) in late-onset AD. In conjunction with this increase in power, we initiated several novel approaches to identify potential AD-related genes. This included stratification of the data into an autopsy-confirmed subset of 199 AD families. Each of these targeted analyses resulted in the identification of novel regions containing potential AD genetic risk factors. Our most significant finding was on chromosome 9 in the autopsy-confirmed subset where we obtained an MLS of 4.31. These approaches, together with new methodologies such as conditional linkage analysis, generalized family-based association tests (PDT), and a new generation of genetic markers (SNPs), opens the door for additional AD gene discovery. Such strategies are necessary if we are to understand the subtle and complex threads that, woven together, create the intricate tapestry of AD.

Age of Onset↗
PubMed2000

Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity.

Apolipoprotein E (APOE) is the only confirmed susceptibility gene for late-onset Alzheimer disease (AD). In a recent genomic screen of 54 families with late-onset AD, we detected significant evidence for a second late-onset AD locus located on chromosome 12 between D12S373 and D12S390. Linkage to this region was strongest in 27 large families with at least one affected individual without an APOE-4 allele, suggesting that APOE and the chromosome 12 locus might have independent effects. We have since genotyped several additional markers across the region, to refine the linkage results. In analyzing these additional data, we have addressed the issue of heterogeneity in the data set by weighting results by clinical and neuropathologic features, sibship size, and APOE genotype. When considering all possible affected sib pairs (ASPs) per nuclear family, we obtained a peak maximum LOD score between D12S1057 and D12S1042. The magnitude and location of the maximum LOD score changed when different weighting schemes were used to control for the number of ASPs contributed by each nuclear family. Using the affected-relative-pair method implemented in GENEHUNTER-PLUS, we obtained a maximum LOD score between D12S398 and D12S1632, 25 cM from the original maximum LOD score. These results indicate that family size influences the location estimate for the chromosome 12 AD gene. The results of conditional linkage analysis by use of GENEHUNTER-PLUS indicated that evidence for linkage to chromosome 12 was stronger in families with affected individuals lacking an APOE-4 allele; much of this evidence came from families with affected individuals with neuropathologic diagnosis of dementia with Lewy bodies (DLB). Taken together, these results indicate that the chromosome 12 locus acts independently of APOE to increase the risk of late-onset familial AD and that it may be associated with the DLB variant of AD.

Age of Onset↗
PubMed2000

Noninvasive blood glucose measurements by near-infrared transmission spectroscopy across human tongues.

Noninvasive blood glucose measurements are characterized in human subjects. A series of first overtone transmission spectra are collected across the tongues of five human subjects with type 1 diabetes. The noninvasive human spectra are collected by an experimental protocol that is designed to minimize chance correlations with blood glucose levels. In one treatment of the data, every fifth sample is used as a blind prediction point to validate model performance. In another rearrangement of the data, the spectra collected over the first 29 days are used to build calibration models that are then used to predict in vivo glycemia from spectra collected over the next 10 days. Of the five data sets (one for each subject), one demonstrates a complete inability to predict blood glucose levels and is deemed void of glucose-specific information. Glucose-specific information is evident in the remaining four data sets, albeit to varying degrees. For all data sets, the ability to measure glucose from spectra collected noninvasively from human subjects depends on spectral quality and reproducibility of the tongue-to-spectrometer interface. The standard error of prediction is 3.4 mM for the best calibration model. The significance of this magnitude of prediction error is discussed relative to the situations where: (1) the model is completely void of glucose-specific information and (2) glucose predictions are limited by spectral signal-to-noise and sample thickness. Overall, glucose-specific information is available from noninvasive first-overtone spectra collected across human tongues. Significant improvements are necessary, however, before clinically useful measurements are possible.

Blood Glucose↗
PubMed2000

Side effects and time course of response in a placebo-controlled trial of fluoxetine for the treatment of geriatric depression.

A high rate of improvement among patients who receive placebo in controlled trials of antidepressants can complicate the evaluation of true drug effect. Placebo response may be a reaction to the psychosocial factors of study participation or a function of changes in the natural course of depression. Drug side effects may also influence patients' expectations, and they should be distinguished from the somatic symptoms associated with major depression. The authors reanalyzed data from a large, multicenter, placebo-controlled clinical trial of fluoxetine treatment of geriatric depression to evaluate similarities and differences between responders and nonresponders in both treatment groups. Specifically, the authors examined weekly somatic complaints as possible predictors of response and of dropout, as well as the time course and onset of response. Fluoxetine was superior to placebo on all outcome measures. Among somatic complaints associated with fluoxetine response, headache before and after randomization was associated with a good response and anxiety after randomization was associated with a poor response. Somnolence before and after randomization was associated with a good placebo response. Early and persistent improvement occurred among similar proportions of responders in both groups. The difference between fluoxetine and placebo seemed to be a persistent response beginning during the 4th week. Pretreatment somnolence was associated with early, persistent improvement in both groups and may serve as a marker for placebo response.

Aged↗
PubMed2000

Dementia diagnostic guidelines: methodologies, results, and implementation costs.

OBJECTIVE: To facilitate the diagnostic process for dementia. Five guidelines and four consensus statements on specific diagnostic recommendations, specialist referral recommendations, and costs of recommended diagnostic procedures were compared and summarized. DATA SOURCES AND SELECTION: A MEDLINE search from 1984 to 1999 and queries to experts yielded 14 guidelines and consensus statements that addressed the diagnosis of dementia. Only nine documents which had national or international scopes were reviewed. METHODS: Comparisons were made on the specific diagnostic criteria for patient history, clinical examination, functional assessment, laboratory tests, neuroimaging, and other diagnostic tests, as well as specialist referral recommendations and costs for the recommended diagnostic procedures. The first three authors reviewed independently each document and completed a table on specific recommendations in each document. To settle disagreements about specific recommendations, they discussed them until they reached a consensus. To interpret the intent of vague statements, they used their best judgment. RESULTS: The documents differed in content, recommendations, and development methodology. They were based on either expert opinion or scientific evidence, or both. Although the nine documents were nearly unanimous in several recommendations, including assessing the presenting problem, taking a medical history, conducting physical and neurological examinations, and assessing the patient's mental and cognitive status, considerable differences in recommendations were common. Such differences led to large differentials in the estimated costs (range, $190 to $2,001) for recommended diagnostic assessments. CONCLUSIONS: A systematic approach to diagnostic recommendations for dementia may induce greater consistency among guidelines and consensus statements. The current approach leads to considerable variability in recommendations and estimated costs.

Consensus Statements as Topic↗
PubMed2000

Investigations into geriatric psychiatry challenges: AAGP Senior Investigator Award 2000.

The author summarizes the American Association for Geriatric Psychiatry Senior Investigator Award presentation delivered at the 13th Annual Meeting March 12-15, 2000, in Miami Beach, Florida, and reviews his research studies that define a trajectory leading to investigations of early detection and prevention of Alzheimer's disease (AD). Themes and critical transitions that fostered the research are emphasized, and effective collaboration, mentoring, and timing are discussed. These studies have combined neuroimaging and genetic methods to identify subjects before they develop AD, so that interventions might delay dementia onset. The eventual goal is to translate the clinical research discoveries into modern clinical practice.

Alleles↗
PubMed1999

Analysis of association between Alzheimer disease and the K variant of butyrylcholinesterase (BCHE-K).

Butyrylcholinesterase (BCHE) is an enzyme expressed in most human tissues. Recently, an increased odds of carrying the K variant of BCHE (BCHE-K) was reported among Alzheimer disease (AD) cases as compared with controls. We tested our data set of 245 sporadic AD cases and 241 controls for an association between BCHE-K, APOE4, and AD using logistic regression and chi-square analyses. The sib transmission disequilibrium test (S-TDT) was also used to test for differences in BCHE-K allele frequencies between 163 discordant sib-pairs selected from multiplex AD families. No statistically significant differences were noted between BCHE-K case and control allele frequencies even after stratifying by APOE4 status. S-TDT analysis between the BCHE-K variant and AD was also not significant (P = 0.52). We conclude that BCHE-K is not a major genetic risk factor for AD in our study population.

Adult↗
PubMed1999

Apolipoprotein E genotype and noncognitive symptoms in Alzheimer's disease.

BACKGROUND: The apolipoprotein E (ApoE) epsilon 4 allele confers significant risk for Alzheimer's disease and is associated with a greater amyloid burden in the brain. Future treatments may target molecular mechanisms associated with this allele, and it is important to define any phenotypic characteristics that correspond to this genotype. We sought to clarify the relationship between ApoE status and noncognitive symptoms in Alzheimer's disease patients. METHODS: Possible and probable Alzheimer's disease patients from a clinical trial (n = 605) were assessed with the 10-item Neuropsychiatric Inventory cross-sectionally prior to treatment, and their ApoE genotype was determined. Among the population studied, the following numbers with specific genotypes were studied: 23-2/3, 17-2/4, 209-3/3, 288-3/4, 68-4/4. RESULTS: When correlations were controlled for the patient's level of cognitive impairment, there was no relationship between epsilon 4 dose and any of the 10 noncognitive symptoms assessed, including psychosis, mood changes, and personality alterations. CONCLUSIONS: Among patients with comparable disease severity, the epsilon 4 allele does not confer additional psychiatric morbidity.

Aged↗
PubMed1999

Crystal structure of bullfrog M ferritin at 2.8 A resolution: analysis of subunit interactions and the binuclear metal center.

Ferritins concentrate and store iron as a mineral in all bacterial, plant, and animal cells. The two ferritin subunit types, H or M (fast) and L (slow), differ in rates of iron uptake and mineralization and assemble in vivo to form heteropolymeric protein shells made up of 24 subunits; H/L subunit ratios reflect cell specificity of H and L subunit gene expression. A diferric peroxo species that is the initial reaction product of Fe(II) in H-type ferritins, as well as in ribonucleotide reductase (R2) and methane monooxygenase hydroxylase (MMOH), has recently been characterized, exploiting the relatively high accumulation of the peroxo intermediate in frog H-subunit type recombinant ferritin with the M sequence. The stability of the diferric reaction centers in R2 and MMOH contrasts with the instability of diferric centers in ferritin, which are precursors of the ferric mineral. We have determined the crystal structure of the homopolymer of recombinant frog M ferritin in two crystal forms: P4(1)2(1)2, a = b = 170.0 A and c = 481.5 A; and P3(1)21, a = b = 210.8 A and c = 328.1 A. The structural model for the trigonal form was refined to a crystallographic R value of 19.0% (Rfree = 19.4%); the two structures have an r.m.s.d. of approximately 0.22 A for all C alpha atoms. Comparison with the previously determined crystal structure of frog L ferritin indicates that the subunit interface at the molecular twofold axes is most variable, which may relate to the presence of the ferroxidase site in H-type ferritin subunits. Two metal ions (Mg) from the crystallization buffer were found in the ferroxidase site of the M ferritin crystals and interact with Glu23, Glu58, His61, Glu103, Gln137 and, unique to the M subunit, Asp140. The data suggest that Gln137 and Asp140 are a vestige of the second GluxxHis site, resulting from single nucleotide mutations of Glu and His codons and giving rise to Ala140 or Ser140 present in other eukaryotic H-type ferritins, by additional single nucleotide mutations. The observation of the Gln137xxAsp140 site in the frog M ferritin accounts for both the instability of the diferric oxy complexes in ferritin compared to MMOH and R2 and the observed kinetic variability of the diferric peroxo species in different H-type ferritin sequences.

Amino Acid Sequence↗
PubMed1999

No association between the HLA-A2 allele and Alzheimer disease.

The apolipoprotein E (APOE)-4 allele is a major risk factor for late-onset Alzheimer disease (AD), but it does not account for all the genetic variation in late-onset AD; thus, other genetic markers must be examined. Previous studies suggest an HLA-A2 allele association with risk and earlier onset age of AD. Because these effects may be additive to those of APOE-4, we studied HLA-A2 and APOE-4 frequencies in AD patients and cognitively intact controls. A total of 712 unrelated Caucasian subjects included 479 patients with AD (435 sporadic, 44 familial) and 233 controls. Patients (mean+/-SD age 73.9+/-7.9 years, range 42-93 years) had probable AD, according to standard diagnostic criteria; controls (mean+/-SD age 70.4+/-8.5 years, range 37-92 years) were cognitively intact. APOE and HLA-A2 typing used polymerase chain reaction to indicate the number of APOE-4 alleles present as well as the presence (A1/A2, A2/A2 genotypes) or absence (A1/A1 genotype) of HLA-A2. A two-way analysis of variance was used to assess the effect of the HLA-A2 allele on age at onset of dementia. No association between HLA-A2 and APOE-4 was found, and the presence of HLA-A2 allele did not increase AD risk. There was also no evidence for an association between HLA-A2 and earlier onset age of AD. Examination age, sex, family history of AD, and recruitment site had no influence on these results. In conclusion, the HLA-A2 allele did not influence AD risk or onset age in this study population. A2 heterozygosity, and population differences, including stratification sub-structures, and other undetermined factors could contribute to discrepant findings among studies.

Adult↗
PubMed1999

Memory self-appraisal in middle-aged and older adults with the apolipoprotein E-4 allele.

OBJECTIVE: Because subjective memory complaints may indicate subtle functional brain abnormalities, the authors studied the influence of the major genetic risk for Alzheimer's disease, the apolipoprotein E-4 (APOE-4) allele, on self-reports of memory performance in middle-aged and older adults. METHOD: Subjective and objective assessments of memory performance were compared in relation to the presence or absence of the APOE-4 allele in 39 cognitively intact persons with mild memory complaints. RESULTS: Subjects with the APOE-4 allele had lower scores on objective verbal memory and on the subjective memory measure for retrospective functioning. Among the subjects in the age range where APOE-4 has its greatest influence on the risk of Alzheimer's disease (55-74 years), the APOE-4 group had lower scores on the subjective memory measure for frequency of forgetting. Moreover, the standardized difference in retrospective functioning scores between the two genetic risk groups increased when the mid-age-range group was examined rather than the whole study group. CONCLUSIONS: The APOE-4 allele is associated with increased subjective memory impairment in middle-aged and older adults. Longitudinal studies of age-related memory loss should include genetic risk and subjective memory measures as potential predictors of decline.

Adult↗