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Change in global and specific measures of cognitive function was studied in a cohort of 410 persons with Alzheimer's disease. Persons completed up to 5 annual evaluations; follow-up participation among survivors exceeded 90%. Average annual decline was 0.57 standard score units (95% confidence interval [CI]: -0.51 to -0.62) on a composite measure based on 17 individual tests and 3.26 points (95% CI: -3.06 to 3.46) on the Mini-Mental State Examination, but substantial heterogeneity was apparent. On both global and specific measures, rate of cognitive decline was reduced in older persons compared with younger persons. A similar effect was observed for estimated age of disease onset. The effect of age was approximately linear and was not attributable to education, sex, race, other conditions that impair cognition, or mortality. The results indicate that person-specific paths of cognitive decline in Alzheimer's disease vary substantially and suggest that in clinical settings some of this variability is related to age. [ABSTRACT FROM AUTHOR]

The contributions of text meaning, new between-word associations, and single-word repetition to priming in text rereading in younger and older adults, and in patients with Alzheimer's disease. (AD), were assessed in Experiment 1. Explicit recognition memory for text was also assessed. Equivalent single-word and between-word priming was observed for all groups, even though patients with AD showed impaired explicit memory for individual words in the text. The contribution of generalized reading task skill to priming in meaningless text rereading in younger adults was assessed in Experiment 2. Generalized reading task skill was also found to contribute to priming. These results reveal 3 mechanisms of priming: new between-word associations for meaningful and meaningless text, individual word repetition for meaningless text, and general task or skill factors for meaningless text. All priming mechanisms appear to be intact in older adults and in patients with AD. [ABSTRACT FROM AUTHOR]

Background Data: Recent literature has suggested that completion axillary lymph node dissection (ALND) in breast carcinoma patients with positive SLN may not be necessary. However, a method for determining the risk of non-SLN or extranodal disease remains to be established., Aims: To determine if pathological variables from primary tumors and sentinel lymph node (SLN) metastases could predict the probability of non-sentinel lymph node (NSLN) metastases and extranodal disease in patients with breast carcinoma and SLN metastases., Methods: 84 women with T1-3 breast cancer and clinically-negative axillae underwent completion ALND. Maximum diameter and width of SLN metastases were measured to calculate metastatic area. When multiple SLNs contained metastases, areas were summed to calculate the Total Metastatic Area (TMA). Multiple linear regression models were used to identify predictive factors., Results: Her-2/neu over-expression increased the odds of NSLN metastases (OR 4.3, p = 0.01) and extranodal disease (OR 7.9, p < 0.001). Independent SLN predictors were ≥1 positive SLN (OR, 7.35), maximum diameter and area of SLN metastases (OR 2.26, 1.85 respectively) and TMA (OR, 2.12). Maximum metastatic diameter/SLN diameter (OR 3.71, p = 0.04) and the area of metastases/SLN area (OR 3.4, p = 0.04) were predictive. For every 1 mm increase in diameter of SLN metastases, the odds of NSLN extranodal disease increased by 8.5% (p = 0.02). TMA >0.40 cm(2) was an independent predictor for NSLN metastases and extranodal disease., Conclusion: Her-2/neu over-expression and parameters assessing metastatic burden in the SLN, particularly TMA, predicted the presence of NSLN involvement and extranodal disease in patients with breast carcinoma and SLN metastases., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Like rituximab, monoclonal antibodies reactive with human leukocyte antigen have potent antilymphoma activity. However, size limits their vascular and tissue penetration. To mimic monoclonal antibody binding, nanomolecules have been synthesized, shown specific for the beta subunit of HLA-DR10, and selective for cells expressing this protein. Selective high affinity ligands (SHALs) containing the 3-(2-([3-chloro-5-trifluoromethyl)-2-pyridinyl]oxy)-anilino)-3-oxopropanionic acid (Ct) ligand residualized and had antilymphoma activity against expressing cells. Herein, we show the extraordinary potency in mice with human lymphoma xenografts of a tridentate SHAL containing this ligand. After titrating antilymphoma activity in cell culture, a randomized preclinical study of a tridentate SHAL containing the Ct ligand was conducted in mice with established and aggressive human lymphoma xenografts. Mice having HLA-DR10 expressing Raji B- or Jurkat's T-lymphoma xenografts were randomly assigned to receive either treatment with SHAL at a dose of 100 ng i.p. weekly for 3 consecutive weeks, or to be untreated. Primary end-points were cure, overall response rates and survival. Toxicity was also evaluated in these mice, and a USFDA general safety study was conducted in healthy Balb/c mice. In Raji cell culture, the threshold and IC50 concentrations for cytotoxic activity were 0.7 and 2.5 nmol (pm/ml media), respectively. When compared to treated Jurkat's xenografts or untreated xenografts, Raji xenografts treated with the SHAL showed an 85% reduction in hazard of death (P=0.014; 95% confidence interval 32-95% reduction). There was no evidence for toxicity even after i.p. doses 2000 times greater than the treatment dose associated with cure of a majority of the mice with Raji xenografts. When compared with control groups, treatment selectively improved response rates and survival in mice with HLA-DR10 expressing human lymphoma xenografts at doses not associated with adverse events and readily achievable in patients.

Alzheimer disease will affect increasing numbers of people as baby boomers (persons born between 1946 and 1964) age. This work reports projections of the incidence of Alzheimer disease(AD) that will occur among older Americans in the future. Education adjusted age-specific incidence rates of clinically diagnosed probable AD were obtained from stratified random samples of residents 65 years of age and older in a geographically defined community. These rates were applied to U.S. Census Bureau projections of the total U.S. population by age and sex to estimate the number of people newly affected each year. The annual number of incident cases is expected to more than double by the midpoint of the twenty-first century: from 377,000 (95% confidence interval = 159,000-595,000) in 1995 to 959,000 (95% confidence interval = 140,000-1,778,000) in 2050. The proportion of new onset cases who are age 85 or older will increase from 40% in 1995 to 62% in 2050 when the youngest of the baby boomers will attain that age. Without progress in preventing or delaying onset of Alzheimer disease, both the number of people with Alzheimer disease and the proportion of the total population affected will increase substantially.

In a population survey on the south-western coast of Norway, 373 never smokers aged 18-73 years (230 women) without respiratory symptoms performed a standardized, progressive, incremental submaximal bicycle exercise test. All individuals were able to do an exercise involving oxygen uptake of 1.0 l min(-1), 80% of the subjects reached 1.5 l min(-1) and 50% of the subjects reached 2.0 l min(-1). The respiratory frequency (RF), ventilation (VE) and heart rate (HR) for a given oxygen uptake were all higher in women than in men. Significant predictors of failure to reach oxygen uptake of 1.5 and 2.0 l min(-1) were sex, age, body height and weight. Prediction equations are given for respiratory frequency, heart rate and ventilation for an oxygen uptake of 1.0 l min(-1) in women and 1.5 l min(-1) in men; and body height is a strong predictor for all dependent variables. A multiple linear regression analysis in women showed that age was a significant predictor of respiratory frequency (P<0.05), ventilation (P<0.001) and heart rate (P<0.001), while in men age was a significant predictor only of ventilation (P<0.001) during the bicycle exercise protocol.

With high resolution, quantitative magnetic resonance imaging (MRI) techniques, it is now possible to examine alterations in brain anatomy in vivo and to identify regions affected in the earliest stages of Alzheimer's disease (AD). In this study, we compared MRI-derived entorhinal and hippocampal volume in healthy elderly controls, patients who presented at the clinic with cognitive complaints, but did not meet criteria for dementia (non-demented), and patients with very mild AD. The two patient groups differed significantly from controls in entorhinal volume, but not from each other; in contrast, they differed from each other, as well as from controls, in hippocampal volume, with the mild AD cases showing the greatest atrophy. Follow-up clinical evaluations available on 23/28 non-demented patients indicated that 12/23 had converted to AD within 12-77 months from the baseline MRI examination. Converters could be best differentiated from non-converters on the basis of entorhinal, but not hippocampal volume. These data suggest that although both the EC and hippocampal formation degenerate before the onset of overt dementia, EC volume is a better predictor of conversion.

We have characterized a novel monoclonal antibody, Tau-66, raised against recombinant human tau. Immunohistochemistry using Tau-66 reveals a somatic-neuronal stain in the superior temporal gyrus (STG) that is more intense in Alzheimer's disease (AD) brain than in normal brain. In hippocampus, Tau-66 yields a pattern similar to STG, except that neurofibrillary lesions are preferentially stained if present. In mild AD cases, Tau-66 stains plaques lacking obvious dystrophic neurites (termed herein 'diffuse reticulated plaques') in STG and the hippocampus. Enzyme-linked immunosorbent assay (ELISA) analysis reveals that Tau-66 is specific for tau, as there is no cross-reactivity with MAP2, tubulin, Abeta(1-40), or Abeta(1-42), although Tau-66 fails to react with tau or any other polypeptide on western blots. The epitope of Tau-66, as assessed by ELISA testing of tau deletion mutants, appears discontinuous, requiring residues 155-244 and 305-314. Tau-66 reactivity exhibits buffer and temperature sensitivity in an ELISA format and is readily abolished by SDS treatment. Taken together these lines of evidence indicate that the Tau-66 epitope is conformation-dependent, perhaps involving a close interaction of the proline-rich and the third microtubule-binding regions. This is the first indication that tau can undergo this novel folding event and that this conformation of tau is involved in AD pathology.

A large proportion of people with Alzheimer's disease (AD) are women; however, it is not clear whether this is due to higher risk of disease or solely to the larger number of women alive at ages when AD is common. Beginning in 1982, two stratified random samples of people aged > or =65 years in East Boston, Massachusetts underwent detailed, structured clinical evaluation for prevalent (467 people) and incident (642 people from a cohort previously ascertained to be disease-free) probable AD. The prevalence sample was followed for mortality for up to 11 years (through December 1992). The age-specific incidence of AD did not differ significantly by sex (for men vs. women, odds ratio = 0.92; 95% confidence interval (CI): 0.51, 1.67). Controlled for age, prevalence also did not differ significantly by sex (for men vs. women, odds ratio = 1.29; 95% CI: 0.67, 2.48). The increase in risk of mortality due to AD did not vary by sex. The odds ratio for women with AD compared with women without AD was 2.07 (95% CI: 1.21, 3.56). For men, the odds ratio was 2.22 (95% CI: 1.02, 4.81). These findings suggest that the excess number of women with AD is due to the longer life expectancy of women rather than sex-specific risk factors for the disease.

Objectives: To examine the prevalence of informal caregiving and demographic factors associated with caregiving time in older community residents and compare caregiving prevalence and time spent providing care by black and white residents., Design: A cross-sectional, population-based study., Setting: The study was conducted as part of the Chicago Health and Aging Project (CHAP) in a geographically defined community of black and white residents aged 65 and older., Participants: Participants were 5,924 community residents (61.4% black; 38.6% white) who answered questions about informal caregiving responsibilities during a structured interview about a broad range of health and social factors., Methods: Data were collected during an in-home interview. Multiple logistic and linear regression models were used to examine the association between caregiving and race, gender, age, marital status, and education., Results: More than 16% of residents had provided care to others during the previous 12 months, and 10.3% were currently providing care. Compared with whites, blacks were 30% more likely to be caregivers, spent almost 13 more hours each week in caregiving activities, and were more likely to assist friends. The probability of caregiving increased significantly with age for married persons, decreased with age for unmarried persons, and was lower for men compared with women. The time spent providing care each week increased significantly with age for married persons and did not differ between men and women., Conclusions: Although physicians and other healthcare providers typically view older people as the recipients of informal care, individuals older than age 65 provide a substantial amount of care to others with health problems and disability. Most research has focused on the needs of young and middle-aged caregivers, and little is known about the needs of these older caregivers. Future research should use sampling strategies that provide adequate numbers of white and non-white participants for meaningful comparisons. This will permit identification of racial and cultural differences in caregiving so that interventions can be tailored to specific groups.

Background: Educational and occupational attainment have been associated with progression of Alzheimer disease in some studies. One hypothesis about this association is that education and occupation are markers for lifelong participation in cognitively stimulating activities like reading., Objective: To assess the relation of premorbid reading activity with patterns of cognitive decline in Alzheimer disease., Methods: During a 4-year period, 410 persons with Alzheimer disease had annual clinical evaluations, which included administration of 17 cognitive function tests from which global, verbal, and nonverbal summary measures were derived. At baseline, a knowledgeable informant was questioned about the affected person's reading frequency and access to reading materials before dementia onset., Results: A composite measure of premorbid reading activity was developed. It had moderately high internal consistency and was positively correlated with education and baseline level of cognitive function. In analyses that controlled for baseline cognitive function, education, and other demographic variables, higher level of premorbid reading activity was associated with more rapid decline on the global cognitive and verbal measures but not on the nonverbal measure., Conclusions: These results suggest that both the extent and nature of premorbid cognitive experiences may affect how Alzheimer disease pathology is clinically expressed.

Background: Late-life depression affects physical health and impedes recovery from physical disability. But whether milder symptoms that occur frequently in the general population increase the risk of developing a disability or decrease the likelihood of recovery remains unclear., Objective: To examine the effect of mild symptoms of depression, assessed by a reduced version (10 items, ranging from 0-10) of the Center for Epidemiological Studies-Depression Scale, on the course of physical disability, assessed by items from the Katz Activities of Daily Living Scale, the Rosow-Breslau Functional Health Scale, and the Nagi Index., Methods: A population-based longitudinal study was conducted, with 6 follow-up interviews of 3434 community-dwelling persons aged 65 years and older in East Boston, Mass., Results: The likelihood of becoming disabled increased with each additional symptom of depression (for the Katz measure: odds ratio, 1.16 per symptom; 95% confidence interval, 1.13-1.19; for the Rosow-Breslau measure: odds ratio, 1.14; 95% confidence interval, 1.11-1.16; and for the Nagi measure: odds ratio, 1.17; 95% confidence interval, 1.14-1.19). As the number of depressive symptoms increased, the likelihood of recovering from a physical disability decreased (for the Katz measure: odds ratio, 0.96; 95% confidence interval, 0.93-0.99; for the Rosow-Breslau measure: odds ratio, 0.86; 95% confidence interval, 0.84-0.89; and for the Nagi measure: odds ratio, 0.89; 95% confidence interval, 0.87-0.91). This effect was not accounted for by age, sex, level of educational attainment, body mass index, or chronic health conditions., Conclusion: Mild depressive symptoms in older persons (those aged > or =65 years) are associated with an increased likelihood of becoming disabled and a decreased chance of recovery, regardless of age, sex, and other factors that contribute to physical disability.

Recent studies indicate that there is a marked reduction in trkA-containing nucleus basalis neurons in end-stage Alzheimer's disease (AD). We used unbiased stereological counting procedures to determine whether these changes extend to individuals with mild cognitive impairment (MCI) without dementia from a cohort of people enrolled in the Religious Orders Study. Thirty people (average age 84.7 years) came to autopsy. All individuals were cognitively tested within 12 months of death (average MMSE 24.2). Clinically, 9 had no cognitive impairment (NCI), 12 were categorized with MCI, and 9 had probable AD The average number of trkA-immunoreactive neurons in persons with NCI was 196, 632 +/- 12,093 (n = 9), for those with MCI it was 106,110 +/- 14,565, and for those with AD it was 86,978 +/- 12,141. Multiple comparisons showed that both those with MCI and those with AD had significant loss in the number of trkA-containing neurons compared to those with NCI (46% decrease for MCI, 56% for AD). An analysis of variance revealed that the total number of neurons containing trkA immunoreactivity was related to diagnostic classification (P < 0.001), with a significant reduction in AD and MCI compared to NCI but without a significant difference between MCI and AD. Cell density was similarly related to diagnostic classification (P < 0.001). There was a significant correlation with the Boston Naming Test and with a global score measure of cognitive function. The number of trkA-immunoreactive neurons was not correlated with MMSE, age at death, education, apolipoprotein E allele status, gender, or Braak score. These data indicate that alterations in the number of nucleus basalis neurons containing trkA immunoreactivity occurs early and are not accelerated from the transition from MCI to mild AD., (Copyright 2000 Wiley-Liss, Inc.)

Alzheimer's disease is a chronic disease, primarily of the elderly, characterized by progressive dementia and eventual death. Community-based studies will likely provide a better representation of the spectrum of disease than will studies drawn solely from clinical sources, because an unknown and possibly substantial fraction of the cases do not come to the attention of the medical care system, or are diagnosed only very late in the disease. Community-based studies will provide not only more accurate estimates of prevalence and incidence, but also more directly comparable unaffected people for studies of risk factors for onset and progression. Such studies are likely to consist of a census component where relatively inexpensive but useful auxiliary information is collected and a probability sample from the census, with the detailed and costly clinical diagnosis of Alzheimer's disease restricted to the sample. The statistician faces challenges both in designing a sample that meets multiple objectives efficiently and in analysing data from the resulting complex survey designs., (Copyright 2000 John Wiley & Sons, Ltd.)

Objective: To assess the relation between parkinsonism and cognitive function in Alzheimer disease from cross-sectional and longitudinal perspectives., Design: Prospective cohort study with annual clinical evaluations during a 4-year period., Setting: Alzheimer disease clinic in an urban medical center., Participants: Four hundred ten persons with clinically diagnosed Alzheimer disease., Main Outcome Measures: Global and specific measures of cognitive function and parkinsonism., Results: Higher levels of parkinsonism at baseline were reliably associated with lower levels of cognitive function at baseline and with more rapid cognitive decline during the 4-year study period. However, the associations were small, with baseline parkinsonism accounting for less than 10% of the variation either in baseline cognitive function or in the rate of cognitive decline. By contrast, rates of change in parkinsonism and cognitive function were strongly correlated, with 70% or more shared variance in the rates of change in many models. The association was observed with diverse measures of cognition and parkinsonism and was not explained by demographic variables or use of neuroleptic medications., Conclusion: In Alzheimer disease, progressive worsening of parkinsonism is more strongly associated with cognitive decline than previously recognized. Arch Neurol. 2000.

Objective: To examine change in cognitive function in older persons sampled from a community population, and its relation to age and Alzheimer disease., Design: Prospective cohort study with an average of 3.5 years of follow-up., Setting: East Boston, Mass--a geographically defined, urban, working-class community., Participants: A stratified, random sample of persons 65 years and older underwent uniform, structured clinical evaluation for Alzheimer disease. The 388 persons (89.2% of those eligible) who completed at least 1 annual follow-up evaluation were studied: 97 had Alzheimer disease at baseline; 95 developed Alzheimer disease during the study; and 196 were unaffected., Outcome Measures: Eight cognitive performance tests were administered, then converted to population-weighted z scores and averaged to create a composite summary measure of cognitive function. Initial level of and change in this score were the outcome measures., Results: In the population as a whole, many persons experienced a decline in cognitive performance, and age was related to both initial level and rate of decline. Analyses were conducted in 3 subgroups: persons with Alzheimer disease at baseline, those who developed Alzheimer disease during the study, and those who remained unaffected. In both Alzheimer disease subgroups, substantial cognitive decline was observed, but neither initial level nor rate of decline was related to age. In unaffected persons, little cognitive decline was evident, and there was a small, inverse association of age with initial level of cognitive function., Conclusion: In a general population sample, there was little evidence of cognitive decline during a 3.5-year period among persons who remained free of Alzheimer disease.

The deposition of beta-amyloid within the entorhinal cortex (EC) may play a key role in the development of mild cognitive impairment (MCI) in the elderly. To examine the relationship of beta-amyloid deposition to MCI, EC tissue immunostained for this protein was quantitated from a cohort of aged Catholic religious clergy with a clinical diagnosis of MCI and compared to those with no cognitive impairment (NCI) and Alzheimer's disease (AD). beta-amyloid staining was seen in 12 of the 20 NCI, in 10 of 12 MCI, and in all 12 AD cases within the EC. beta-amyloid immunoreactivity displayed two patterns within the EC: (1) a crescent-shaped band within layers 3-4 or (2) bilaminar staining mainly within layers 2-3 and 5-6. Ten cases failed to display any detectable beta-amyloid imunoreactivity. Despite the heterogeneity of beta-amyloid loads within the clinical groups, decomposing an analysis of variance revealed a significant difference across groups in mean beta-amyloid load within the EC based upon a linear trend analysis. Multiple comparisons testing revealed that NCI individuals had a significantly lower mean beta-amyloid load (1.32) than AD individuals (4.55). The MCI individuals had a mean intermediate (2.60) load between NCI and AD, but not statistically distinguishable from the mean for either NCI or AD. Spearman rank correlation showed a trend for decreasing MMSE with increasing amyloid load that failed to reach statistical significance. Since many NCI cases displayed beta-amyloid loads equal to or greater than that seen in some MCI and some AD cases, it is mostly likely that deposition of this protein is not the sole pathogenic event underlying cognitive impairment in the elderly., (Copyright 1999 Academic Press.)

Objectives: There is considerable evidence that social networks are strongly related to survival and other health outcomes. However, findings regarding the effect of social networks on disability outcomes have been inconsistent. This study examines this relationship with respect to the risk of developing disability and recovering from disability., Methods: Data come from a community-based sample of the New Haven population aged 65 years and older, with nine annual interviews conducted between 1982 and 1991. Disability was measured by a 6-item index of activities of daily living (ADL), and a 3-item Rosow-Breslau index, with disability defined as impairment in one or more tasks on each measure. Social network variables were constructed for each of four domains of ties: children, relatives, friends, and a confidant, and a summary measure of total social networks. A Markov model was used to estimate one-year disability transitions averaged across all 8 intervals, after controlling for sociodemographic and health-related variables., Results: Total social networks was associated with a significantly reduced risk of developing ADL disability (beta = -0.009, p < .01), and a significantly increased likelihood of ADL recovery (beta = 0.017, p < .01). Emotional and instrumental support did not affect the protective effect of social networks against disability, but partially accounted for their effect on enhanced recovery. Network variables related to relatives and friends were significantly associated with disability and recovery risks, but those related to children or a confidant were not. The associations with disability transitions as measured by the Rosow-Breslau index were generally smaller and nonsignificant., Discussion: The findings lend further support for the role of social relationships in important health outcomes in old age. They suggest that being "embedded" in a social network of relatives and friends reduces risk for ADL disability, and enhances recovery from ADL disability.

Context: Previous studies raise the possibility that blood pressure (BP) in middle age predicts later cognitive decline., Objective: To examine prospectively the relationship of BP with level of and change in cognitive function in the elderly., Design: Longitudinal, population-based study comprising subjects enrolled in the East Boston component of the Established Populations for the Epidemiologic Study of the Elderly (EPESE) (1982-1983) and the Hypertension Detection and Follow-Up Program (HDFP) (1973-1974)., Setting: East Boston, Mass., Participants: Of the 3657 participants in the EPESE with baseline BP measurements, 2068 also participated in the HDFP. Subjects were aged 65 to 102 years at baseline in the EPESE and had mental status and memory assessed at baseline and 3 and 6 years., Main Outcome Measures: Numbers of errors on the Short Portable Mental Status Questionnaire and the East Boston Memory Test and rates of change in these numbers of errors. Subjects had BP measured both at baseline in the EPESE and 9 years before, as part of the HDFP., Results: In analyses adjusted for age, sex, and education, there was no strong linear association between BP and cognition. The associations found were fairly small in magnitude, and varied according to which test was used to measure cognition. There was little evidence for an effect of BP on change in cognitive function with either test, or for an effect on level of function on the memory test. In analyses of level of mental status questionnaire performance, however, elevated systolic BP (> or =160 mm Hg) 9 years before baseline was associated with a 14% (95% confidence interval [CI], 4%-25%) increase in error rate, relative to the referent (130-139 mm Hg). Baseline systolic BP had a U-shaped association with the number of errors; error rates were 9% higher compared with the referent group among those with systolic BP lower than 130 mm Hg (95% CI, 1%-17%) and 7% greater (95% CI, 0%-15%) among those with elevated systolic BP. Diastolic BP 9 years before baseline also had a U-shaped association with errors on the mental status questionnaire., Conclusion: The findings do not suggest a linear association of BP with cognitive decline, but they are consistent with a more complex relationship between BP and cognition than previously appreciated.

Oxidative stress may play a role in neurologic disease. The present study examined the relation between use of vitamin E and vitamin C and incident Alzheimer disease in a prospective study of 633 persons 65 years and older. A stratified random sample was selected from a disease-free population. At baseline, all vitamin supplements taken in the previous 2 weeks were identified by direct inspection. After an average follow-up period of 4.3 years, 91 of the sample participants with vitamin information met accepted criteria for the clinical diagnosis of Alzheimer disease. None of the 27 vitamin E supplement users had Alzheimer disease compared with 3.9 predicted based on the crude observed incidence among nonusers (p = 0.04) and 2.5 predicted based on age, sex, years of education, and length of follow-up interval (p = 0.23). None of the 23 vitamin C supplement users had Alzheimer disease compared with 3.3 predicted based on the crude observed incidence among nonusers (p = 0.10) and 3.2 predicted adjusted for age, sex, education, and follow-up interval (p = 0.04). There was no relation between Alzheimer disease and use of multivitamins. These data suggest that use of the higher-dose vitamin E and vitamin C supplements may lower the risk of Alzheimer disease.

Objective: To examine the relationship between psychotic symptoms and subsequent physically aggressive behavior in outpatients with Alzheimer's disease., Design: This observational study used a time series design to measure the presence and frequency of physically aggressive behavior over a 52-week period. Multiple regression models were used to evaluate delusions and hallucinations, assessed at baseline, as predictors of physical aggression, controlling for demographic and clinical variables., Setting and Participants: Of 315 consecutive eligible outpatients from the Rush Alzheimer's Disease Center, referred for evaluation for dementia, 270 (86%) participated in the study. All participants met NINCDS/ADRDA criteria for probable Alzheimer's disease; Mini-Mental State Examination scores ranged from 0 to 27, with a mean of 14.9 (SD = 5.6)., Measurements: Psychotic symptoms, previous episodes of physical aggression, and demographic variables were measured at baseline through a structured interview with an informant living in the same household. Physically aggressive behavior was measured sequentially at 1-week intervals over a period of 52 consecutive weeks and also through structured informant interviews., Results: A total of 75 persons had one or more episodes of physical aggression during the 52 weeks of observation. The presence of delusions significantly predicted the presence and frequency of physical aggression. Of participants with high rates of physical aggression (> 1 episode/month), 80% had delusions. This effect was robust, even after controlling for the effects of other clinical variables. By contrast, hallucinations did not reliably predict episodes of physical aggression., Conclusions: These data suggest that delusions, but not hallucinations, predict physically aggressive behavior in persons with Alzheimer's disease. In light of the persecutory nature of most delusional ideation in Alzheimer's disease, delusions may be associated with distortions in the perception of threat in common social situations.

This study compared the odds of becoming disabled and recovering from disability among blacks and whites aged 65 years and over in two sites of the Established Populations for Epidemiologic Studies of the Elderly (EPESE) project. The authors examined the influence of mortality differences, socioeconomic status, and health-related factors on racial differences in risk of disability and recovery. A Markov model was employed using nine waves of data from the New Haven, Connecticut, site (529 blacks, 2,219 whites) and seven waves of the North Carolina (Piedmont) site (2,260 blacks, 1,876 whites), collected between 1982 and 1992. Blacks below age 75 years had an increased risk of developing disability relative to whites in New Haven (odds ratio (OR) at age 65 years = 3.33, 95% confidence interval (CI) 2.13-5.22) as well as in North Carolina (OR at age 65 years = 1.58, 95% CI 1.25-1.99). This excess risk diminished with increasing age, and crossed over in New Haven (OR at age 85 years = 0.45, 95% CI 0.22-0.95), but not in North Carolina (OR at age 85 years = 1.22, 95% CI 0.98-1.51). Adjustment for socioeconomic and health-related factors only partially reduced the excess disability risk among blacks below age 75 years in New Haven, but eliminated the difference in disability risk between blacks and whites in North Carolina. Blacks below age 75 years also had higher mortality risks at both sites. There were no consistent racial differences in recovery from disability.

Background: Older people frequently have signs of parkinsonism, but information about the prevalence of parkinsonism and mortality among those with the condition in the community is limited., Methods: A stratified random sample of 467 residents of East Boston, Massachusetts, 65 years of age or older, were given structured neurologic examinations. Using uniform, specified combinations of parkinsonian signs, we estimated the prevalence of four categories of signs--bradykinesia, gait disturbance, rigidity, and tremor--and of parkinsonism, defined as the presence of two or more categories. We did not study Parkinson's disease because it could not be distinguished from other conditions that can cause parkinsonism. Proportional-hazards models were used to compare the risk of death among people with and those without parkinsonism., Results: One hundred fifty-nine persons had parkinsonism, 301 did not, and 7 could not be classified. The overall prevalence estimates were 14.9 percent for people 65 to 74 years of age, 29.5 percent for those 75 to 84, and 52.4 percent for those 85 and older. With a mean follow-up period of 9.2 years, 124 persons with parkinsonism (78 percent) and 146 persons without (49 percent) died. Adjusted for age and sex, the overall risk of death among people with parkinsonism was 2.0 (95 percent confidence interval, 1.6 to 2.6) times that among people without. Among people with parkinsonism, the presence of gait disturbance was associated with an increased risk of death., Conclusions: Parkinsonism is very common among people over the age of 65, and its prevalence increases markedly with age. Parkinsonism is associated with a twofold increase in the risk of death, which is strongly related to the presence of a gait disturbance.

Objective: To determine age-specific incidence rates of clinically diagnosed Alzheimer's disease., Design: Cohort, followed a mean of 4.3 years., Setting: East Boston, Mass., Participants: Of 2313 persons aged 65 years and older who were initially free of Alzheimer's disease, 1601 participated in the ascertainment of incident disease (80% of survivors), 409 declined participation, and 303 died before the end of the follow-up period. A stratified sample of 642 persons received detailed clinical evaluation., Outcome Measure: Diagnosis of new probable Alzheimer's disease through structured clinical evaluation including neurologic, neuropsychological, and psychiatric examination. Community incidence rates were computed by 5-year age groups, adjusted for gender, single year of age, length of follow-up interval, and sampling design., Results: The estimated annual incidence of Alzheimer's disease in the population was 0.6% (95% confidence interval [CI], 0.3% to 0.9%) for persons aged 65 to 69 years, 1.0% (95% CI, 0.6% to 1.4%) for persons aged 70 to 74 years, 2.0% (95% CI, 1.3% to 2.7%) for persons aged 75 to 79 years, 3.3% (95% CI, 2.2% to 4.4%) for persons aged 80 to 84 years, and 8.4% (95% CI, 3.7% to 13.1%) for persons aged 85 years and older., Conclusions: The incidence of Alzheimer's disease is substantial and is approximately 14 times higher among persons older than 85 years compared with those between 65 and 69 years of age.

Serum p24 antigen levels were examined in subjects from three clinical trials of zidovudine to determine whether the pattern of change in serum p24 antigen during the first 8-16 weeks of therapy was associated with human immunodeficiency virus type 1 (HIV-1) disease progression or death. Among 406 patients with AIDS and a first episode of Pneumocystis carinii pneumonia, 65% had measurable pretreatment concentrations of serum p24 antigen (> or = 10 pg/mL). Changes during treatment were not associated with reduced mortality. In 637 mildly symptomatic patients, 24% had measurable concentrations, and changes were marginally associated with increased time until more advanced disease. Among 683 asymptomatic patients, 18% had measurable concentrations, and changes were not associated with increased time until progression. Despite the small number of clinical events and the low rate of serum p24 antigen positivity in the latter two studies, pretreatment serum p24 antigen levels were predictive of clinical outcome; subsequent measurements appear to be of limited use in evaluating zidovudine therapy.

Objective: Virtually all estimates of the prevalence and incidence of incontinence in the community rely on self-reported continence status. The goal of this study was to assess the reliability of this measure in older adults., Design: Telephone interviews administered approximately 2 weeks apart., Setting: Community-based congregate living facility., Participants: A convenience sample of approximately 100 residents was contacted by letter; 48 of 51 (94%) who indicated their willingness to participate were interviewed. They included eight men and 40 women > 70 years old (79% > 80 years old), virtually all of whom were independent in basic ADLs and 83% of whom reported their health as good or excellent., Measurement: Responses to a structured questionnaire., Main Results: The prevalence of urinary incontinence was 40% at baseline and 44% on re-interview; the prevalence of fecal incontinence was 17% on both occasions. All Spearman correlations for items related to urinary incontinence characteristics were between .80 and .86, except for a question related to stress incontinence (r = .62); correlations for fecal incontinence were .67-.69., Conclusion: Prevalence estimates of incontinence are stable over a 2-week period. However, the variability of individual responses, while relatively low, was within the range previously reported for estimates of incidence and remission rates of incontinence in community-dwelling elderly. This, variability should be taken into consideration when interpreting previous studies and designing future ones.

Tumor necrosis factor-alpha (TNF)-cachectin increases the expression of the human immunodeficiency virus (HIV), reverses the therapeutic efficacy of zidovudine (ZDV), and may contribute to the wasting syndrome. Pentoxifylline (Trental) decreases TNF activity; in cell culture, it decreases HIV replication and down-regulates expression of the HIV long terminal repeat (LTR). Therefore, pentoxifylline was administered to 25 patients with advanced AIDS in this AIDS Clinical Trial Group study (ACTG #160), the goal of which was to investigate the ability of the drug to decrease TNF expression and HIV replication in this patient population. One patient discontinued drug treatment because of toxicity. Data were analyzed on the 17 patients who completed the 8-week study treatment with pentoxifylline, 400 mg, thrice daily. The median pretreatment CD4+ lymphocyte count was 32 cells/mm3. Fasting serum triglycerides, which have previously been shown to correlate with levels of interferon-alpha and/or TNF, fell on average by 66 mg/dl (p = 0.06). TNF mRNA levels in peripheral blood mononuclear cells fell in 10 of 16 patients (p = 0.02). HIV load decreased and increased significantly in four and one patients, respectively, but did not change in the group as a whole. This study demonstrates the safety of pentoxifylline in AIDS patients and its ability to decrease triglycerides and TNF mRNA levels.

In a community population of persons over the age of 65, cognitive function was assessed using brief performance tests on two occasions 3 years apart. Those with fewer years of formal education consistently had greater declines in cognitive function, independently of age, birthplace, language of interview, occupation, and income. These prospective findings suggest that low educational attainment or a correlate predicts cognitive decline. It is not clear, however, whether this relation represents a direct effect of education on future cognition, whether education might be related to occurrence of a disease leading to cognitive decline in older persons, or whether education might be a surrogate for some variable not included in the study.

We report results from the first part of an ongoing longitudinal study aimed at identifying the relative contributions of demographic, seizure, and family variables in the prediction of behavior problems in children with epilepsy. We studied 127 children with epilepsy aged 8-12 years and their mothers. Self-report questionnaires, interviews, and medical records were data sources. Backward and forward stepwise elimination procedures using multiple regression indicated five variables that contributed significantly to prediction of behavior problems: female gender, family stress, family mastery, extended family social support, and seizure frequency. These factors accounted for 29% (p < 0.001) of the variation in behavioral problems. Findings suggest that family variables are important correlates of behavior problems and should be considered in clinical management of children with epilepsy.

The correlation coefficient between initial and subsequent blood pressure (BP) measurements is referred to as the tracking correlation. Childhood BP tracking correlations, although positive, have been considered too low to make accurate predictions for an individual. These correlations, however, can be raised substantially by averaging BP over multiple weekly visits in each year, which partially accounts for within-person variability. In a cohort of 333 school children, we measured BP 3 times on each of 4 successive weekly visits, in each of 4 consecutive years, using a random-zero sphygmomanometer. Approximately 90 per cent of subjects had data for one or more follow-up years, and 75 per cent of subjects who entered in the first year had data for all four years. With a model that allows estimation of correlations and that uses all available longitudinal data, we calculated tracking correlations completely corrected for within-person variability, the statistical equivalent of measuring BP on an infinite number (infinity) of visits and measurements per visit. Age-sex adjusted tracking correlations for 3 years of follow-up based on the means from 1,2,3,4, and infinity visits are, for systolic BP, 0.43, 0.56, 0.62, 0.66, and 0.73, respectively, and for diastolic BP, 0.20, 0.37, 0.46, 0.50, and 0.70, respectively. With longer follow-up, the use of corrected tracking correlations would allow determination of the maximal extent to which childhood BP can predict adult levels, and therefore the usefulness of screening to identify children at high risk of developing hypertension.

Epidemiologic studies are often designed to severe several purposes. The complex sampling plans necessary to ensure an adequate number of cases, a similar age distribution among cases and controls, or other important design constraints for comparative studies may make the additional goal of estimating prevalence in the population or in important subgroups difficult to attain with existing computer software, which typically assumes simple random sample selection. We consider here various methods for estimating overall and subgroup prevalence from complex samples, including crude prevalences, direct standardization of prevalences, and standardization using logistic regression to smooth the sampling group prevalences. We illustrate these methods using a complex sample to estimate the prevalence of Alzheimer's disease in an urban community. A simulation study under various models in this setting is also described. We conclude that the use of logistic regression to smooth sampling group prevalences before standardization is an effective method for estimation of overall prevalence, provided that the adequacy of fit of a logistic model is carefully checked.

The human immunodeficiency virus establishes an intimate interaction with the immune system. The virus can use cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (Il-1), to regulate its own expression by modifying the normal immunoregulatory network. We demonstrate that mRNA of the cytokine TNF-alpha from peripheral blood mononuclear cells is overexpressed in virtually all patients with AIDS who do not have active opportunistic infections compared with uninfected volunteers (p < 0.0001). This overexpression correlates with elevated mRNA levels of the recently discovered GRO (p < 0.05), a cytokine involved in the inflammatory response.