Prospective Evaluation of Cognitive Health and Related Factors in Elderly at Risk for Developing Alzheimer's Dementia: A Longitudinal Cohort Study.

BACKGROUND: The CHARIOT PRO Main study is a prospective, non-interventional study evaluating cognitive trajectories in participants at the preclinical stage of Alzheimer's disease (AD) classified by risk levels for developing mild cognitive impairment due to AD (MCI-AD). OBJECTIVES: The study aimed to characterize factors and markers influencing cognitive and functional progression among individuals at-risk for developing MCI-AD, and examine data for more precise predictors of cognitive change, particularly in relation to APOE ε4 subgroup. DESIGN: This single-site study was conducted at the Imperial College London (ICL) in the United Kingdom. Participants 60 to 85 years of age were classified as high, medium (amnestic or non-amnestic) or low risk for developing MCI-AD based on RBANS z-scores. A series of clinical outcome assessments (COAs) on factors influencing baseline cognitive changes were collected in each of the instrument categories of cognition, lifestyle exposure, mood, and sleep. Data collection was planned to occur every 6 months for 48 months, however the median follow-up time was 18.1 months due to early termination of study by the sponsor. RESULTS: 987 participants were screened, among them 690 participants were actively followed-up post baseline, of whom 165 (23.9%) were APOE ε4 carriers; with at least one copy of the allele. The mean age was 68.73 years, 94.6% were white, 57.4% were female, and 34.8% had a Family History of Dementia with a somewhat larger percentage in the APOE ε4 carrier group (42.4%) compared to the non-carrier group (32.4%). Over half of the participants were married and 53% had a Bachelor's or higher degree. Most frequently, safety events typical for this population consisted of upper respiratory tract infection (10.4%), falls (5.2%), hypertension (3.5%) and back pain (3.0%). Conclusion (clinical relevance): AD-related measures collected during the CHARIOT PRO Main study will allow identification and evaluation of AD risk factors and markers associated with cognitive performance from the pre-clinical stage. Evaluating the psycho-biological characteristics of these pre-symptomatic individuals in relation to their natural neurocognitive trajectories will enhance current understanding on determinants of the initial signs of cognitive changes linked to AD.

Psychometric Evaluation of the Neuropsychological Test Battery in Individuals with Normal Cognition, Mild Cognitive Impairment, or Mild to Moderate Alzheimer's Disease: Results from a Longitudinal Study.

BACKGROUND: The Neuropsychological Test Battery (NTB) is a combination of widely used clinical neuropsychological tests measuring memory and executive function and was designed to overcome some of the limitations of the traditionally used Alzheimer's disease Assessment Scale - Cognitive subscale (ADAS-Cog). A previously reported account indicated high levels of NTB reliability in patients with mild-to-moderate Alzheimer's disease (AD) and mild cognitive impairment (MCI). OBJECTIVES: We examined capacity of the Neuropsychological Test Battery (NTB) and its component subtests to measure cognitive change over time. Correlations with other cognitive and functional assessments were also determined. Design, Settings, Participants: This was a multicentre, prospective, non-interventional, longitudinal cohort study involving patients with mild-to-moderate AD (n=196), MCI (n=70), or cognitively normal control participants (NC, n=75). INTERVENTION: The NTB, as well as other Clinical Outcome Assessments including, ADAS-Cog, other cognitive measures, functional/behavioral questionnaires, health outcome questionnaires, and resource utilization tools were administered. RESULTS: Mean change from baseline for the NTB composite score and the six individual NTB subtests showed greater reductions in performance over time in the AD and MCI groups, compared with NC group. The ADAS-Cog was found to be more sensitive to change than the NTB in all three populations. CONCLUSIONS: The NTB showed high correlation with the ADAS-Cog and appears to be a sensitive and reliable assessment tool for measuring cognitive decline in patients with mild-to-moderate AD. However, the ADAS-Cog was found to be more sensitive to change over time in both the AD and MCI populations.

MR imaging features of amyloid-related imaging abnormalities.

BACKGROUND AND PURPOSE: AD is one of the few leading causes of death without a disease-modifying drug; however, hopeful agents are in various phases of development. MR imaging abnormalities, collectively referred to as amyloid-related imaging abnormalities, have been reported for several agents that target cerebral Aß burden. ARIA includes ARIA-E, parenchymal or sulcal hyperintensities on FLAIR indicative of parenchymal edema or sulcal effusions, and ARIA-H, hypointense regions on gradient recalled-echo/T2* indicative of hemosiderin deposition. This report describes imaging characteristics of ARIA-E and ARIA-H identified during studies of bapineuzumab, a humanized monoclonal antibody against Aß. MATERIALS AND METHODS: Two neuroradiologists with knowledge of imaging changes reflective of ARIA reviewed MR imaging scans from 210 bapineuzumab-treated patients derived from 3 phase 2 studies. Each central reader interpreted the studies independently, and discrepancies were resolved by consensus. The inter-reader κ was 0.76, with 94% agreement between neuroradiologists regarding the presence or absence of ARIA-E in individual patients. RESULTS: Thirty-six patients were identified with incident ARIA-E (17.1%, 36/210) and 26 with incident ARIA-H (12.4%, 26/210); of those with incident ARIA-H, 24 had incident microhemorrhages and 2 had incident large superficial hemosiderin deposits. CONCLUSIONS: In 49% of cases of ARIA-E, there was the associated appearance of ARIA-H. In treated patients without ARIA-E, the risk for incident blood products was 4%. This association between ARIA-E and ARIA-H may suggest a common pathophysiologic mechanism. Familiarity with ARIA should permit radiologists and clinicians to recognize and communicate ARIA findings more reliably for optimal patient management.

An MRI rating scale for amyloid-related imaging abnormalities with edema or effusion.

BACKGROUND AND PURPOSE: Immune therapy against amyloid-ß appears to be a promising target in Alzheimer disease. However, a dose-related risk for ARIA on FLAIR images thought to represent parenchymal vasogenic edema or sulcal effusion (termed "ARIA-E"), has been observed in clinical trials. To assess the intensity of ARIA-E presentation, an MR imaging scale that is both reproducible and easily implemented would assist in monitoring and evaluating this adverse event. MATERIALS AND METHODS: On the basis of a review of existing cases from a phase II bapineuzumab study, a scale was constructed with a 6-point score for the 6 regions on each side of the brain (range, 0-60). Scores would be obtained for both parenchymal and sulcal hyperintensities and frequently co-occurring gyral swelling. Inter-rater reliability between 2 neuroradiologists was evaluated in 20 patients, 10 with known ARIA-E and 10 without, by using the intraclass correlation coefficient. RESULTS: The 2 raters had excellent agreement in the identification of ARIA-E cases. A high inter-rater agreement was observed for scores of parenchymal hyperintensity (ICC = 0.83; 95% CI, 48-96) and sulcal hyperintensity (ICC = 0.89; 95% CI, 63-97) and for the combined scores of the 2 ARIA-E findings (ICC = 0.89; 95% CI, 62-97). Gyral swelling scores were observed to have lower inter-rater agreement (ICC = 0.54; 95% CI, -0.06-0.86). CONCLUSIONS: The proposed rating scale provides a reliable and easily implemented instrument to grade ARIA-E imaging findings. We currently do not recommend including swelling.

Correlates of osteoprotegerin levels in women and men.

Osteoprotegerin (OPG) is a potent antiresorptive molecule that binds the final effector for osteoclastogenesis, receptor activator of NF-kappaB ligand (RANK-L). OPG production is regulated by a number of cytokines and hormones, including sex steroids, but there are few data on age and gender effects on circulating serum OPG levels, as well as possible relationships between OPG levels and bone turnover markers or bone mineral density (BMD). Thus, we measured serum OPG levels in an age-stratified, random sample of men (n = 346 age range, 23-90 years) and women (n = 304; age range 21-93 years) and related them to sex steroid levels, bone turnover markers and BMD. Serum OPG levels increased with age in both men (R = 0.39, p < 0.001) and women (R = 0.18, p < 0.01). Premenopausal women had higher OPG levels than men under age 50 years (171 +/- 6 pg/ml vs 134 +/- 6 pg/ml, respectively, p < 0.001), whereas serum OPG levels were no different in postmenopausal women compared with men = 50 years (195 +/- 7 pg/ml vs 188 +/- 7 pg/ml, respectively, p = 0.179). OPG levels correlated inversely with serum bioavailable testosterone levels in men = 50 years (R = -0.27, p < 0.001), but no associations were present with either estrogen or testosterone levels in the women. In the men, there was a trend for OPG levels to be associated positively with bone resorption markers and inversely with BMD. Collectively, the gender difference in OPG levels suggests that sex steroids may regulate OPG production in vivo, as has been found in vitro. Moreover, OPG production may also rise with increases in bone turnover, probably as a homeostatic mechanism to limit bone loss. Further studies directly testing these hypotheses should provide additional insights into the potential role of OPG in bone loss related to aging and sex steroid deficiency.

Does arsenic exposure increase the risk for circulatory disease?

Studies of residents in communities with high endemic concentrations of arsenic in drinking water suggest a deleterious effect on the circulatory system; however, studies among workers with high occupational exposures generally have shown either no or weak associations. This discrepancy could be a result of the healthy worker effect, including the healthy hire component and the healthy worker survivor effect (HWSE). Therefore, the authors conducted analyses of arsenic exposure in relation to circulatory disease mortality among 2,802 Tacoma, Washington, smelter workers by using 1) internal comparisons to control for the healthy hire effect and 2) the lagging method, adjustment for employment status, and the G-null test to control for the HWSE. Both lagging and adjustment for work status increased circulatory mortality rate ratios at all exposure levels, as compared with a baseline Poisson model. This excess mortality was limited to cardiovascular disease; no excess was observed for cerebrovascular disease. G-null analyses suggested no adverse effect, but power was very limited for this analysis. Overall, these results may indicate that the HWSE obscures an effect of arsenic on circulatory disease. Since cardiovascular deaths constitute about one-third of total mortality, small rate ratios translate into large numbers of excess deaths and, if causal, could be of wide public health significance. Further studies of arsenic exposure and cardiovascular disease are needed, and those conducted in occupational cohorts must control for the HWSE.

The impact of asthma and asthma-like illness in Seattle school children.

The impact of asthma and asthma-like illness was measured in a population of 5-9-year-old Seattle public school children. Child health information was obtained from a survey of 1665 parents of first and second grade students to assess medical services use and impaired physical functioning among diagnosed asthmatics and those with current wheezing, defined as wheezing in the past 12 months without a diagnosis of asthma, relative to an asymptomatic population with neither condition. Relative to the asymptomatic population, the prevalence of respiratory-related activity limitation, and perception of poorer child health was larger among diagnosed asthmatics than children with current wheezing. However, the prevalence of sleep disturbances, school absences, medical services use, and parental concern over their child's health was similar for both the asthmatic and wheezing groups relative to the asymptomatic group. Also, in both symptomatic groups, a history of moderate or severe wheezing was associated with an increased prevalence of respiratory-related sleep disturbances and activity limitation. The similarity between the impact of diagnosed asthma and undiagnosed asthma-like illness suggests that the overall social and economic burden of asthma may be higher than previously estimated.

Indoor risk factors for asthma and wheezing among Seattle school children.

Indoor risk factors for physician-diagnosed asthma and wheezing in the past 12 months without previous asthma diagnosis were assessed in a survey of parents of 5-9-year-old Seattle primary school students. Among the 925 respondents, 106 (11%) reported a physician diagnosis of asthma, 66 (7%) had wheezing without diagnosis, and 753 (82%) were asymptomatic. After adjusting for age, sex, gender, ethnicity, medical history, socioeconomic status (SES) and parental asthma status, an increased risk of physician diagnosis of asthma was associated with household water damage, the presence of one or more household tobacco smokers, and at least occasional environmental tobacco smoke (ETS) exposure. Similarly, an increased risk of wheezing in the past 12 months among children without diagnosed asthma was associated with household water damage, presence of one or more household tobacco smokers, and occasional or more frequent ETS exposure. No increased risk of either condition was associated with gas, wood, or kerosene stove use, household mold, basement water, or wall/window dampness. Similarities in the indoor risk factors patterns between diagnosed asthma and wheezing without diagnosis suggested a similar etiology of these two conditions. The slightly higher association between ETS and asthma may indicate that parents of diagnosed asthmatics were more conscious of ETS, and were more likely to prohibit household smoking by resident smokers. Future research is needed to quantify which aspects of household water damage are related to respiratory illness.

A cost of illness study of allergic rhinitis in the United States.

BACKGROUND: Allergic rhinitis is a common condition, but the burden of this condition on the national economy is not well understood. OBJECTIVE: The purpose of this study was to estimate the national direct and indirect costs of allergic rhinitis. METHODS: Data from the National Medical Expenditure Survey were used to provide estimates of resource utilization, medical expenditures, and lost productivity. With the complex survey design, variance estimates were used to construct confidence intervals for cost estimates of resource utilization and lost productivity. RESULTS: It is estimated that approximately 39 million persons in the United States experienced allergic rhinitis in 1987. However, only 12.3% (4.8 million) sought medical treatment for allergic rhinitis. The total estimated cost of the condition, in 1994 dollars, was $1.23 billion (95% confidence interval, $846 million to $1.62 billion). Direct medical expenses accounted for 94% of total costs. Allergic rhinitis results in approximately 811,000 missed workdays, 824,000 missed school days, and 4,230,000 reduced activity days. CONCLUSION: Allergic rhinitis clearly creates a burden in terms of the number of persons affected, total expenditures, and lost productivity. It also appears that a relatively large proportion of persons with allergic rhinitis were not seeking medical treatment.

Controlling the healthy worker survivor effect: an example of arsenic exposure and respiratory cancer.

OBJECTIVE: This investigation sought to examine whether methods proposed to control the healthy worker survivor effect would influence the shape or magnitude of the dose-response curve for respiratory cancer induced by arsenic. METHODS: Results from an unadjusted analysis are compared with results obtained by applying four different methods for control of the healthy worker survivor effect to data on arsenic exposure and respiratory cancer. The four methods are: exposure lag, adjustment for work status, cohort restriction, and the G null test. RESULTS: Cohort restriction gave erratic results depending upon the minimum years of follow up used. Exposure lag substantially increased the rate ratios and a non-linear shape (decreasing slope) compared with an unlagged analysis. Adjusting for work status (currently employed upsilon retired or otherwise not employed) yielded slightly higher rate ratios than an unadjusted analysis, with an overall shape similar to the baseline analysis. Results from the G null test procedure of Robins (1986), although not directly comparable with the baseline analysis, did show an adverse effect of exposure that seemed to reach a maximum when exposure was lagged between 10 and 20 years. CONCLUSIONS: All results confirm an adverse effect of arsenic exposure on respiratory cancer. In these data, it seems that the healthy worker survivor effect was not strong enough to mask the strong effect of arsenic exposure on respiratory cancer. Nevertheless, several methods show a stronger association between arsenic exposure and respiratory cancer after adjustment for the healthy worker survivor effect, suggesting that for weaker causal associations, studies not controlling for this source of bias will have low power to detect results. Although the G methods are theoretically the most unbiased, further work elucidating the validity of the assumptions underlying lagging, adjustment for work status, and the G methods are needed before clear recommendations can be made.

Controlling for time-since-hire in occupational studies using internal comparisons and cumulative exposure.

Employees within an occupational cohort may demonstrate a more favorable mortality experience while maintaining employment than those who leave employment. At the same time, they may experience an apparent decline in health with time-since-hire. The time-since-hire effect may occur independently of exposure but may nevertheless result in groups categorized by cumulative exposure that are not comparable. Controlling for time-since-hire appears to solve this problem. To quantify the empirical bias in estimates of exposure effect due to confounding from time-since-hire, we analyzed two occupational cohorts using Poisson regression with and without adjustment for time-since-hire or time-since-start-of-follow-up. In a cohort exposed to airborne arsenic, a strong dose-response relation with respiratory cancer mortality had been established. In a cohort exposed to external, penetrating ionizing radiation, a weak and controversial dose-response relation had been reported. The parameter estimates relating exposure to disease from the models that explicitly adjusted for time-since-hire or time-since-start-of-follow-up are within 10% of the estimates from models that did not. It appears, from this empirical analysis of two datasets, that occupational studies may not need to adjust explicitly for such time-related factors as time-since-hire or time-since-start-of-follow-up if these are implicitly controlled through other variables in the model.

US asthma mortality: 1941 to 1989.

BACKGROUND: Asthma mortality in the United States has nearly doubled in the past 10 years. An examination of long-term trends in United States asthma mortality places the current mortality rates in a historical perspective, identifies high-risk groups for interventions, and may provide clues to the etiology of asthma mortality. METHODS: Asthma deaths for the population aged 5 to 34 years were abstracted from United States vital statistics reports for the period 1941 through 1989. Race-specific and sex-specific mortality rates were age-adjusted to the 1989 estimate of the US population. RESULTS: Among the population aged 5 to 34 years, three distinct periods of asthma mortality were observed: 1941 to 1964, 1965 to 1977, and 1978 to 1989. From 1941 through 1964, nonwhites exhibited a gradual increase in asthma mortality rates; in contrast, whites showed no change in mortality rates. From 1965 through 1977, a marked decline in mortality rates was observed among both nonwhites and whites. From 1978 through 1989, asthma mortality increased with a near doubling in the mortality rates in both nonwhites and whites. Overall, nonwhites had mortality rates 4 times those of whites, with nonwhite males aged 15 to 34 at the greatest risk of death due to asthma. Age and sex differences in asthma mortality are also apparent. The population aged 15 to 34 years generally had mortality rates greater than the population aged less than 15 years. For the population aged 5 to 14 years, regardless of calendar year, females had lower mortality rates than males. Among the population aged 15 to 34 years, females experienced twice the mortality rates of males prior to 1965; however, by the 1980s this relationship no longer existed. CONCLUSIONS: The asthma mortality rate for nonwhites was 4-fold higher than for whites, although the reported prevalence of asthma is less than 2-fold greater. The population aged 15 to 34 years had higher mortality rates than the population aged 5 to 14 years despite exhibiting a lower prevalence of asthma. There are also gender differences in asthma mortality. These differences may be attributable to differences in asthma severity, or differences in disease management or reflect actual differences in mortality. These findings suggest that the search for clues to understand the increase in asthma mortality from 1978 to 1989 should include an attempt to understand why asthma mortality declined in the preceding decade from 1967 to 1977 as these may not be completely unrelated trends.

The evolving concept of the healthy worker survivor effect.

The "healthy worker survivor effect" describes a continuing selection process such that those who remain employed tend to be healthier than those who leave employment. In an analysis of exposure-response patterns in an occupational study, the healthy worker survivor effect generally attenuates an adverse effect of exposure. In practical terms, such attenuation will be more problematic when evaluating subtle rather than strong associations. The use of an internal referent does not guarantee elimination of this effect, since by definition, it manifests within an occupational cohort. Although documented over 100 years ago, there is little consensus regarding the most appropriate method to control for the healthy worker survivor effect. Four methods have been proposed for its control: (1) restriction of the cohort to survivors of a fixed number of years of follow-up, (2) lagging the exposure to exclude recent exposure incurred by those who remained on the job, (3) adjusting for employment status as a confounder, and (4) treating the healthy worker survivor effect simultaneously as an intermediate and confounding variable by means of the G-null test or its extension, G-estimation analysis, using structurally nested failure time models. This paper reviews the concept of the healthy worker survivor effect and the four methods to control for it.

Natural history of prostatism: urinary flow rates in a community-based study.

Urinary flow rates were measured in a randomly selected community sample of more than 2,000 men 40 to 79 years old with no history of prostate surgery, prostate cancer or certain other diseases known to interfere with normal voiding. Peak urinary flow rates decreased from a median of 20.3 ml. per second in men 40 to 44 years old to 11.5 ml. per second for men 75 to 79 years old, while voided volumes decreased from a median of 355.5 to 222.5 ml. for the same age ranges. Peak flow rates of less than 10 ml. per second were found in 6% of the men aged 40 to 44 years, increasing to 35% among men aged 75 to 79 years. Urological standards for peak urinary flow rate should be based on community data, and should account for age and voided volume. Our study may serve as the starting point for the development of community-based flow rate normal ranges. Nomograms are given to permit estimating flow rate percentiles as a function of age and voided volume.

Natural history of benign prostatic hyperplasia and risk of prostatectomy. The Baltimore Longitudinal Study of Aging.

The natural history of prostatism (clinically diagnosed benign prostatic hyperplasia) is examined based on symptom questionnaires and digital rectal examinations administered periodically to 1,057 men followed prospectively for up to thirty years in the Baltimore Longitudinal Study of Aging (BLSA). Benign prostatic hyperplasia (BPH) was clinically diagnosed in 527 men, 110 had a prostatectomy for BPH, and in 21 prostate cancer developed. Among men aged sixty or older with prostatic enlargement and obstructive symptoms, the twenty-year probability of surgery was 39 percent; for men aged fifty to fifty-nine years this probability was 24 percent; and for men aged forty to forty-nine years, the probability was 13 percent. The age-specific prevalence of clinically diagnosed BPH agreed closely at all ages with the age-specific autopsy prevalence of pathologically defined BPH from a published international compilation of 5 independent autopsy studies involving 1,075 prostates.

Symptoms and signs of prostatism as risk factors for prostatectomy.

Symptom questionnaires and physical examinations administered periodically to 1,057 men followed prospectively for up to 30 years in the Baltimore Longitudinal Study of Aging (BLSA) were analyzed to determine which symptoms of prostatism were predictive of subsequent prostatectomy for benign prostatic hyperplasia (BPH). Change in the size and force of the urinary stream (P = 0.0001) and a sensation of incomplete emptying (P = 0.0005) were the only symptoms positively predictive in a multivariate analysis. Prostate enlargement by rectal palpation was an independent risk factor for prostatectomy (P less than 0.03) and was associated with hesitancy (P less than 0.02) and a sensation of incomplete emptying (P less than 0.02). Of the men with all three risk factors, 37% (41/112) eventually had a prostatectomy, in contrast to 8% of the remaining 945 men. This is the first study to document the extent to which urologic symptoms and a digital rectal examination predict subsequent prostatectomy for BPH.

Cumulative prevalence of prostatism matches the autopsy prevalence of benign prostatic hyperplasia.

The age-specific cumulative prevalence of clinically diagnosed prostatism among 1,057 generally healthy men followed for up to 30 years in the Baltimore Longitudinal Study of Aging was compared with the age-specific autopsy prevalence of pathologically defined benign prostatic hyperplasia (BPH) from a published compilation of five independent autopsy studies involving 1,075 prostates. Clinical prevalences based on medical histories and digital rectal examinations showed excellent agreement with autopsy prevalences at all ages. Despite the well-known lack of correspondence between prostatism and objective urologic evidence of BPH in individual patients, these results suggest that the proportion of the male population with clinically recognizable prostatism by a given age is about the same as the proportion with pathological evidence of BPH.