Immune response to influenza vaccination in community-dwelling Chinese elderly persons.

We investigated the immune antibody response to influenza vaccine in community-dwelling Chinese elderly persons in Hong Kong. One hundred and twenty-eight subjects were recruited in a single-blind, randomized, and placebo-controlled trial. There was no significant baseline difference between the vaccine and placebo groups regarding the seroprotection rates (PR) (haemagglutination inhibition [HI] titre>or=1:40) and geometric mean titres (GMT) of the HI antibody titers. The PR, GMTs and serological response rates increased significantly in the vaccinated versus placebo groups in A-H1N1 at both weeks 4 and month 6. The GMTs and serological response rates but not the PR for A-H3N2 and influenza B increased significantly in vaccinated versus placebo group at week 4 and month 6 post-vaccination. Multivariate logistic regression analyses of the seroconversion rate for A-H3N2 within the vaccinated group showed that gender, coronary heart disease and the serum albumin level were significant predictors (p=0.018, 0.009 and 0.025, respectively). Influenza vaccination provoked a protective HI antibody response in community-living Chinese elderly persons. The mean number of unplanned hospital admissions per subject over 6 months was significantly lower in the vaccinated than in the placebo groups. Hospitalized elderly persons had poorer nutrition, 4-week post-immunization HI antibody titres and lower mini-mental state examination (MMSE) score than non-hospitalized elderly persons. Logistic regression analyses showed that chronic obstructive airway disease significantly increased the risk of hospitalization while the serum albumin level and 4-week A-H3N2 PR (HI>or=40) were independent predictors of a decreased risk of hospitalizations.

Polymorphisms in the bone morphogenetic protein 2 (BMP2) gene do not affect bone mineral density in white men or women.

INTRODUCTION: Peak bone mineral density (BMD) achieved during adulthood is a major determinant of osteoporotic fracture in later life. Although environmental factors affect peak BMD, it is a highly heritable trait. Recently, bone morphogenetic protein 2 (BMP2) was reported as a susceptibility gene for osteoporotic fractures and low BMD in Icelandic and Danish populations. METHODS: To determine whether polymorphisms in the BMP2 gene contribute to BMD variation in our population of healthy American whites, we tested seven single nucleotide polymorphisms (SNPs), four of which were associated with osteoporotic phenotypes in the previous study. BMD at the femoral neck and lumbar spine (L2-L4) were measured by dual energy X-ray absorptiometry (DXA) in 411 men (age 18-61) and 1,291 pre-menopausal women (age 20-50). SNP genotypes/haplotypes were tested for population-based association with BMD using analysis of variance. RESULTS: None of the polymorphisms tested reached statistical significance (all p values >0.05) for BMD at the femoral neck or lumbar spine in either gender. Two of the SNP haplotypes spanning the entire BMP2 gene were marginally associated with BMD in men (p values=0.019-0.043). However, these haplotypes would account for only a small, if any, portion of BMD variation and would not be significant after adjustment for multiple comparisons. CONCLUSIONS: These results demonstrate that genetic variations in BMP2 do not substantially contribute to BMD variation in our population of healthy American whites.

The relationship between non-cognitive symptoms and functional impairment in Alzheimer's disease.

OBJECTIVE: Cognitive impairment is an important determinant for functional impairment in Alzheimer's disease. The role of non-cognitive symptom is uncertain. The objective of this study was to investigate the role of non-cognitive symptoms as predictive factors for functional outcome in A.D. METHODS: This was a retrospective study. Subjects were recruited from the Memory Clinic in Queen Mary Hospital over a two years period. Patients with diagnosis of probable A.D. by NINCDS-ADRDA were identified. Demographic data, Folstein Mini-Mental Status Examination (MMSE), Clinical Dementia Rating (CDR), Neuropsychiatric inventory (NPI), Barthel activities of daily living (ADL) as well as Lawton's Instrumental activities of daily living (IADL) were retrieved. RESULTS: 100 patients were identified. Univariate analysis identified statistically significant correlation between hallucination and disinhibition score with Barthel Index (r=-0.43, p <0.001; r=-0.30, p=0.002 respectively); hallucination and aberrant motor act score with Lawton's IADL (r=-0.21, p=0.038; r=-0.21, p=0.038). MMSE was statistical significantly correlated with the above two functional scores. NPI was not statistical significantly correlated with any one of the functional measures. Multivariate regression analyses showed that hallucination score was an independent predictive factors for the Barthel index but not for the Lawton's IADL. MMSE score was identified to be independent predictive factor for all functional measures. CONCLUSIONS: Global cognitive impairment and hallucination was an important independent predictive factor for functional outcomes. Screening hallucination during the course of A.D. would be helpful. Further studies are needed to show the benefit of treatment of hallucination on the improvement of functional outcomes.

Linkage of structure at the proximal femur to chromosomes 3, 7, 8, and 19.

Risk for osteoporotic fracture is determined in part by femoral structure, which is under genetic control. We conducted a genome scan in 638 sister-pairs for structure phenotypes. Significant evidence of linkage was detected with several chromosomal regions, including confirmation of our prior linkage findings. Bone strength and resistance to fracture at the proximal femur is determined in part by structural variables. We previously reported that several structural variables, including pelvic axis length, femur axis length, femur head width, and femur midshaft width, had significant or suggestive linkage to regions of chromosomes 3, 4, 5, 7, 9, 17, and 19 in a sample of 309 white premenopausal sister pairs. We now report the results of a genome-wide linkage analysis of femoral structure variables in 437 white and 201 black healthy premenopausal sister pairs, of which 191 white pairs overlapped with our previously published sample. Multipoint quantitative linkage analysis was performed using microsatellite markers genotyped throughout the genome. In the current sample, linkage of femoral structure to chromosomes 3, 7, and 19 was confirmed in the white sister pairs, and a new linkage to chromosome 8 was identified. There was linkage at chromosome 3 to femoral head width (logarithm of the odds [LOD] = 5.0) and femur shaft width (LOD = 3.6). On chromosome 19, there was linkage to femoral neck axis length (LOD = 3.2); on chromosome 7, to femoral head width (LOD = 5.0); and on chromosome 8, to femoral head width (LOD = 6.0). The current findings emphasize the importance of increasing sample size to replicate linkage findings and identify new regions of linkage.

Prevalence of cognitive impairment: data from the Indianapolis Study of Health and Aging.

BACKGROUND: The epidemiology and natural history of cognitive impairment that is not dementia is important to the understanding of normal aging and dementia. OBJECTIVE: To determine the prevalence and outcome of cognitive impairment that is not dementia in an elderly African American population. METHOD: A two-phase, longitudinal study of aging and dementia. A total of 2212 community-dwelling African American residents of Indianapolis, IN, aged 65 and older were screened, and a subset (n = 351) received full clinical assessment and diagnosis. Subsets of the clinically assessed were seen again for clinical assessment and rediagnosis at 18 and 48 months. Weighted logistic regression was used to generate age-specific prevalence estimates. RESULTS: The overall rate of cognitive impairment among community-dwelling elderly was 23.4%. Age-specific rates indicate increasing prevalence with increasing age: 19.2% for ages 65 to 74 years, 27.6% for ages 75 to 84 years, and 38.0% for ages 85+ years. The most frequent cause of cognitive impairment was medically unexplained memory loss with a community prevalence of 12.5%, followed by medical illness-associated cognitive impairment (4.0% prevalence), stroke (3.6% prevalence), and alcohol abuse (1.5% prevalence). At 18-month follow-up, 26% (17/66) of the subjects had become demented. CONCLUSIONS: Cognitive impairment short of dementia affects nearly one in four community-dwelling elders and is a major risk factor for later development of dementia.

Genome screen for quantitative trait loci underlying normal variation in femoral structure.

Femoral structure contributes to bone strength at the proximal femur and predicts hip fracture risk independently of bone mass. Quantitative components of femoral structure are highly heritable traits. To identify genetic loci underlying variation in these structural phenotypes, we conducted an autosomal genome screen in 309 white sister pairs. Seven structural variables were measured from femoral radiographs and used in multipoint sib-pair linkage analyses. Three chromosomal regions were identified with significant evidence of linkage (log10 of the odds ratio [LOD] > 3.6) to at least one femoral structure phenotype. The maximum LOD score of 4.3 was obtained for femur neck axis length on chromosome 5q. Evidence of linkage to chromosome 4q was found with both femur neck axis length (LOD = 3.9) and midfemur width (LOD = 3.5). Significant evidence of linkage also was found to chromosome 17q, with a LOD score of 3.6 for femur head width. Two additional chromosomal regions 3q and 19p gave suggestive (LOD > 2.2) evidence of linkage with at least two of the structure phenotypes. Chromosome 3 showed evidence of linkage with pelvic axis length (LOD = 3.1), midfemur width (LOD = 2.8), and femur head width (LOD = 2.3), spanning a broad (60 cm) region of chromosome 3q. Linkage to chromosome 19 was supported by two phenotypes, femur neck axis length (LOD = 2.8) and femur head width (LOD = 2.8). This study is the first genome screen for loci underlying variation in femoral structure and represents an important step toward identifying genes contributing to the risk of osteoporotic hip fracture in the general population.

A randomized controlled trial of low-dose recombinant human growth hormone in the treatment of malnourished elderly medical patients.

High-dose recombinant human GH (rhGH) has been shown to improve the nutritional status of malnourished older adults. It is uncertain whether low-dose rhGH is effective and whether its effect on nutritional status will lead to any improvement in physical function. There is also no data on the outcome after a short course of rhGH treatment. The objectives of this study were to determine the efficacy of low-dose rhGH treatment for 4 weeks in malnourished elderly patients, its effect on physical functions, and the intermediate term outcome after a 4-week rhGH treatment. The study design was a randomized, placebo-controlled, double-blind trial conducted in a university teaching hospital. The patients were 19 medically stable malnourished elderly subjects. Intervention in the rhGH group was as follows: rhGH (Saizen, Serono, Switzerland) 0.09 IU/kg body weight (BW) 3 times weekly were given together with appropriate dietary intervention as prescribed by the dietitian. In the placebo group, equal volumes of normal saline per kilogram BW were given 3 times weekly together with the dietary intervention. The baseline demographic, anthropometric, nutritional, and hematological variables, measures of physical function, and insulin-like growth factor I levels in both groups were comparable. Compared with the placebo group, the GH-treated group showed a more rapid gain in BW (after 3 weeks, +1.27 +/- 0.36 vs. -0.28 +/- 0.37 kg; P = 0.008), total lean body mass (change after 3 weeks by bio-impedance analysis, +1.45 +/- 0.36 vs. -0.37 +/- 0.48 kg; P = 0.009) and a faster improvement in 5-m walking time (decrease after 4 weeks, 23.79 +/- 9.41 vs. 0.45 +/- 4.62 sec; P = 0.047). The hemoglobin level rose more in the rhGH than the placebo groups (change at 8 weeks, +0.84 +/- 0.34 vs. -0.42 +/- 0.29 g/dL; P = 0.012). Serum albumin level also showed a greater delayed increase in the rhGH group than in the placebo group (change at 8 weeks, +5.1 +/- 0.8 vs. 1.6 +/- 1.2 g/dL; P = 0.023). There was no statistically significant difference for other nutritional variables. There was a greater rise in the mean serum insulin-like growth factor I level at 4 weeks in the GH than in the placebo groups (197 +/- 58 vs. 54 +/- 26 U/L; P = 0.034). The improvement in the rhGH group gradually diminished on follow-up and became statistically insignificant 8 weeks after stopping rhGH treatment. There were no GH-related adverse effects. Low-dose rhGH was an effective and safe adjuvant to dietary augmentation for stable malnourished elderly subjects. It led to a faster gain in total lean body mass, which was associated with greater improvement in walking speed when compared with dietary intervention alone. There were no apparent side effects.

Incidence of dementia and Alzheimer disease in 2 communities: Yoruba residing in Ibadan, Nigeria, and African Americans residing in Indianapolis, Indiana.

CONTEXT: Alzheimer disease (AD) represents a major and increasing public health problem. If populations were identified with significantly lower or higher incidence rates of AD, the search for risk factors in the genesis of AD could be greatly enhanced. OBJECTIVE: To compare incidence rates of dementia and AD in 2 diverse, elderly community-dwelling populations. DESIGN: The Indianapolis-Ibadan Dementia Project, a longitudinal, prospective population-based study consisting of a baseline survey (1992-1993) and 2 subsequent follow-up waves after 2 years (1994-1995) and 5 years (1997-1998). Each wave followed a 2-stage design, with an in-home screening interview followed by a full diagnostic workup of a subsample of participants based on screening performance. SETTING AND PARTICIPANTS: A total of 2459 community-dwelling Yoruba residents of Ibadan, Nigeria, without dementia, and 2147 community-dwelling African American residents of Indianapolis, Ind, without dementia (all aged 65 years or older). The cohorts were followed up for a mean of 5.1 years and 4.7 years, respectively. MAIN OUTCOME MEASURES: Incident cases of dementia and AD in each of the 2 populations. RESULTS: The age-standardized annual incidence rates were significantly lower among Yoruba than among African Americans for dementia (Yoruba, 1.35% [95% confidence interval [CI], 1.13%-1.56%]; African Americans, 3.24% [95% CI, 2.11%-4.38%]) and for AD (Yoruba, 1.15% [95% CI, 0.96%-1.35%]; African Americans, 2.52% [95% CI, 1.40%-3.64%]). CONCLUSION: This is the first report of incidence rate differences for dementia and AD in studies of 2 populations from nonindustrialized and industrialized countries using identical methods and the same group of investigators in both sites. Further explorations of these population differences may identify potentially modifiable environmental or genetic factors to account for site differences in dementia and AD.

The reliability and validity of the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) among the elderly Chinese in Hong Kong.

INTRODUCTION: The Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) was reported to be a sensitive cognitive function assessment scale for Alzheimer's Disease (AD). The English, Greek, Spanish but not Chinese versions had been validated previously. OBJECTIVES: The objectives of the present study were to investigate the reliability and validity of an adapted Chinese version of the ADAS-cog among Chinese elderly AD patients in Hong Kong. MATERIALS AND METHOD: Thirty-nine subjects were recruited during the period July to December 1998. Twenty were AD patients while 19 were non-demented normal subjects. Two raters administered the ADAS-cog scale thrice on different occasions. RESULTS: The internal consistency (Cronbach's alpha) of the ADAS-cog were 0.91, 0.88 and 0.65 for the whole group, the AD and normal (i.e. non-demented) subjects respectively. The test-retest reliability as measured by the Spearman's rho correlation coefficients were 0.96, 0.86 and 0.86 for the whole group, AD and normal subjects, respectively, (all P < 0.001). The Spearman's rho correlation coefficients for inter-rater reliability were 0.95 (P < 0.001), 0.91 (P < 0.001) and 0.65 (P = 0.003) for the whole group, AD and normal subjects, respectively. The ADAS-cog score was inversely related to the Mini-Mental Status Examination (MMSE) score (Spearman's rho = -0.91; P < 0.001). The ADAS-cog score was directly proportional to the Clinical Dementia Rating (CDR) (rho = 0.89; P < 0.001). Forward stepwise discriminant function analysis between AD and normal subjects yielded a canonical discriminant function with 3-question items (i.e. word recall test, orientation and comprehension of speech; P < 0.001). This short version had a sensitivity of 90%, specificity of 94.7% and overall accuracy of 92.3%. CONCLUSION: The Chinese version of ADAS-cog subscale is both reliable and valid among the elderly Chinese in Hong Kong.

Genome screen for QTLs contributing to normal variation in bone mineral density and osteoporosis.

A major determinant of the risk for osteoporosis is peak bone mineral density (BMD), which is largely determined by genetic factors. We recently reported linkage of peak BMD in a large sample of healthy sister pairs to chromosome 11q12-13. To identify additional loci underlying normal variations in peak BMD, we conducted an autosomal genome screen in 429 Caucasian sister pairs. Multipoint LOD scores were computed for BMD at four skeletal sites. Chromosomal regions with LOD scores above 1.85 were further pursued in an expanded sample of 595 sister pairs (464 Caucasians and 131 African-Americans). The highest LOD score attained in the expanded sample was 3.86 at chromosome 1q21-23 with lumbar spine BMD. Chromosome 5q33-35 gave a LOD score of 2.23 with femoral neck BMD. At chromosome 6p11-12, the 464 Caucasian pairs achieved a LOD score of 2.13 with lumbar spine BMD. Markers within the 11q12-13 region continued to support linkage to femoral neck BMD, although the peak LOD score was decreased to 2.16 in the sample of 595 sibling pairs. Our study is the largest genome screen to date for genes underlying variations in peak BMD and represents an important step toward identifying genes contributing to osteoporosis in the general population.

Estimating disease prevalence from two-phase surveys with non-response at the second phase.

In this paper we compare several methods for estimating population disease prevalence from data collected by two-phase sampling when there is non-response at the second phase. The traditional weighting type estimator requires the missing completely at random assumption and may yield biased estimates if the assumption does not hold. We review two approaches and propose one new approach to adjust for non-response assuming that the non-response depends on a set of covariates collected at the first phase: an adjusted weighting type estimator using estimated response probability from a response model; a modelling type estimator using predicted disease probability from a disease model; and a regression type estimator combining the adjusted weighting type estimator and the modelling type estimator. These estimators are illustrated using data from an Alzheimer's disease study in two populations.

Sib pair linkage and association studies between bone mineral density and the interleukin-6 gene locus.

A major determinant of the risk for osteoporosis in later life is bone mineral density (BMD) attained during early adulthood. Bone mineral density is a complex trait that, presumably, is influenced by multiple genes. Interleukin-6 (IL-6) is an attractive candidate gene for osteoporosis susceptibility, because it has effects on bone cells and has been implicated in the pathogenesis of osteoporosis. Furthermore, previous investigators have identified an association between a 3' UTR polymorphism of the IL-6 gene and BMD. In this study, we searched for linkage and association between this IL-6 gene polymorphism and peak BMD in a large population (812 individuals) of healthy premenopausal sibpairs. Although previous investigators identified only 6 IL-6 alleles, we identified 17 alleles by modifying electrophoretic conditions and evaluating a very large population. We found no evidence for either linkage or association between the IL-6 gene locus and BMD of the spine or hip in either Caucasians or African Americans.

Estimating the incidence of dementia from two-phase sampling with non-ignorable missing data.

Two-phase sampling designs have been used in the field of psychiatry to estimate prevalence and incidence of a rare disease such as dementia and Alzheimer's disease. In a longitudinal study on dementia, since the repeated two-phase sampling is conducted several years after the baseline wave, some subjects may die before the follow-up wave, thus their disease status prior to death is missing. There are reasons to suggest that the missing due to death is non-ignorable. Estimation of disease incidence from longitudinal dementia study has to appropriately adjust for data missing by death as well as the sampling design used at each study wave. In this paper we adopt a selection model approach to model the missing data by death and use a likelihood approach to derive incidence estimates. A modified EM algorithm is used to deal with data from sampling selection. The non-parametric jack-knife variance estimator is used to derive variance estimates for the model parameters and the incidence estimates. The proposed approaches are applied to data from the Indianapolis-Ibadan Dementia Study.

Spacing of follow-up waves in incidence studies.

Longitudinal studies of dementia are often undertaken to estimate the incidence of dementia and to identify incident cases for the study of risk factors measured on the entire cohort at baseline. The power of these analyses is determined primarily by the number of demented cases identified. Increasing the number of waves of evaluation of the cohort in a given time period increases the yield of demented cases but it also increases the cost of the study. This paper provides a method for estimating dementia incidence in the presence of mortality and loss to follow-up. It also assesses the trade-off between the cost (as measured by the number of re-evaluations) and the yield of incident dementia cases so that longitudinal studies of dementia can be designed optimally in the future.

A quality control measure for longitudinal studies with continuous outcomes.

At the time of data acquisition in a longitudinal study a decision needs to be made whether or not the latest measurement of the primary outcome is a potential outlier. If the data point does not fit with the subject's prior data, the patient can be immediately remeasured before he/she leaves the office. From the third visit onwards, a least squares approach can be used to generate prediction intervals for the value of the response at that visit. We propose a Bayesian method for calculating a prediction interval that can incorporate external information about the process that can be used beginning at the first visit. Both the least squares and Bayesian approaches will be used to prospectively clean longitudinal data. An example using longitudinally measured bone density measurements in the elderly will be discussed. In addition, simulation studies will be described which show that both cleaning methods are better than doing nothing and that the Bayesian approach outperforms the least squares method.

Sibling pair linkage and association studies between bone mineral density and the insulin-like growth factor I gene locus.

A major determinant of the risk for osteoporosis in later life is bone mineral density (BMD) attained during early adulthood. BMD is a complex trait that presumably is influenced by multiple genes. Insulin-like growth factor I (IGF-I) is an attractive candidate gene for osteoporosis susceptibility, because IGF-I has marked effects on bone cells and has been implicated in the pathogenesis of osteoporosis. The IGF-I gene contains a microsatellite repeat polymorphism approximately 1 kb upstream from the IGF-I gene transcription start site, and previous investigators have found a higher prevalence of the 192/192 genotype of this polymorphism among men with idiopathic osteoporosis compared to controls. In this study we used this IGF-I polymorphism to test for an association between this polymorphism and BMD in our large population of premenopausal women (1 sister randomly chosen from 292 Caucasian and 71 African-American families). We also used this polymorphism to detect linkage to BMD elsewhere in the IGF-I gene or in a nearby gene using sibling pair linkage analysis in healthy premenopausal sister pairs (542 sibling pairs: 418 Caucasian and 124 African-American). Neither test provided any evidence of linkage or association between the IGF-I gene locus and spine or femoral neck BMD in Caucasians or African-Americans.

Rates of growth and loss of bone mineral in the spine and femoral neck in white females.

This study characterizes the rates of growth and loss of bone mass as a function of age in white females. It combines longitudinal data from several studies of bone mass on healthy white female subjects ranging from age 6 to 90 years. Rates of change in bone area, bone mineral content (BMC) and bone mineral density (BMD) are estimated separately for the spine and the femoral neck of each individual using linear regression. The individual rates of change are then fitted as a nonparametric function of age using weighted moving averages, resulting in a curve of age-specific mean change as a function of age. When the curves of BMD were compared between the hip and the femoral neck, the cessation of bone growth and the onset of bone loss were found to occur at an earlier age at the hip than at the spine. No significant differences in the ages of maximum rates of growth or maximum loss were found between the two skeletal sites. This information will be useful for designing interventions to promote bone growth or retard bone loss.

Association of antioxidants with memory in a multiethnic elderly sample using the Third National Health and Nutrition Examination Survey.

Oxidative stress has been implicated both in the aging process and in the pathological changes associated with Alzheimer's disease. Antioxidants, which have been shown to reduce oxidative stress in vitro, may represent a set of potentially modifiable protective factors for poor memory, which is a major component of the dementing disorders. The authors investigated the association between serum antioxidant (vitamins E, C, A, carotenoids, selenium) levels and poor memory performance in an elderly, multiethnic sample of the United States. The sample consisted of 4,809 non-Hispanic White, non-Hispanic Black, and Mexican-American elderly who visited the Mobile Examination Center during the Third National Health and Nutrition Examination Survey, a national cross-sectional survey conducted from 1988 to 1994. Memory is assessed using delayed recall (six points from a story and three words) with poor memory being defined as a combined score less than 4. Decreasing serum levels of vitamin E per unit of cholesterol were consistently associated with increasing levels of poor memory after adjustment for age, education, income, vascular risk factors, and other trace elements and minerals. Serum levels of vitamins A and C, beta-carotene, and selenium were not associated with poor memory performance in this study.

Comparing two prevalence rates in a two-phase design study.

An epidemiological study often uses a two-phase design to estimate the prevalence rate of a mental disease. In a two-phase design study, the first phase assesses a large sample with an inexpensive screening test, and then the second phase selects a subsample for a more expensive diagnostic evaluation. Furthermore, disease status may not be ascertained for all subjects who are selected for disease verification because some subjects are unable to be clinically assessed, while others may refuse. Since not all screened subjects are selected for diagnostic assessments, there is potential for verification bias. In this paper, we propose the maximum likelihood (ML) and bootstrap methods to correct for verification bias for estimating and comparing the prevalence rates under the missing-at-random (MAR) assumption for the verification mechanism. We also propose a method to test this MAR assumption. Finally, we apply our methods to a large-scale prevalence study of dementia disorders.