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Objectives: To examine the effect of social engagement (SE) on mortality in long-term care., Design: A retrospective cohort study., Setting: A 725-bed long-term care facility., Participants: A total of 927 long-term care residents who had SE measurements and did not have a serious communication problem., Measurements: Minimum Data Set information including psychosocial items comprising an internally reliable and valid SE scale, and mortality risk factor measurements. Mortality data during the 1,721-day follow-up period was obtained from facility records., Results: Life table analyses indicate that higher levels of SE are associated with longer survival (P = .0001). Unadjusted proportional hazards analyses show that residents who did not engage socially were 2.3 times more likely to die during the follow-up period compared with residents who were the most socially engaged. Multivariate adjusted analyses showed the protective effect of SE on mortality remained even after simultaneously adjusting for mortality risk factors. Residents who did not engage socially were 1.4 times as likely to die during the follow-up period compared with residents who were the most socially engaged., Conclusions: Increased levels of SE were associated with longer survival independent of mortality risk factors. SE may be a modifiable risk factor for death among long-term care residents. More research is needed to understand psychological factors that may influence residents' desire and ability to engage socially.

Background: Postprandial hypotension (PPH) is a common and morbid problem in elderly people that is associated with an impaired vascular response to meal digestion. Healthy aging in the absence of blood pressure elevation is associated with autonomic and neurohumoral changes that may influence the vascular response to meal ingestion. However, it is not known whether these age-related changes are associated with the development of PPH., Methods: We measured hemodynamic (blood pressure, heart rate, and forearm vascular resistance), autonomic (power spectral analysis of heart rate and blood pressure variability), and neurohumoral (plasma norepinephrine, renin, aldosterone, and endothelin) responses to a mixed 425 kilocalorie (kcal) meal in 89 rigorously screened healthy subjects aged 20-39, 40-59, and 60-83 years., Results: After the meal, supine mean arterial blood pressure fell significantly only in the middle-aged group by 5.4 +/- 7.9 mm Hg at 30 minutes (p = .02). Forearm vascular resistance fell after the meal in all age groups ( p = .0001). Older groups had higher plasma norepinephrine (p = .02), lower heart rate (p = .03), lower cardiovagal activity (p = .0001), and lower sympathetic vasomotor (p = .000) activity, but there was no difference in the response of these variables to a meal., Conclusion: Healthy aging, in the absence of blood pressure elevation, alters the level of autonomic activity without further impairing the ability to maintain blood pressure during meal digestion. Hemodynamic, autonomic, and neurohumoral responses to meal ingestion remain unchanged in very healthy, normotensive elderly adults.

Purpose: Constipation is a common complaint among geriatric patients and may result in significant morbidity, especially among nursing home residents. The prevalence of constipation increases with advancing age and may be a result of the aging process, but the exact cause is unknown. The aim of this study was to describe the prevalence of constipation and to determine risk factors for the development of constipation in a large population of nursing home residents., Methods: The Minimum Data Set is an assessment instrument used in nearly all Medicare-certified and Medicaid-certified nursing facilities. Nursing home residents who were at least 65 years of age and who had assessments at baseline and at three months were included in the study (N = 21,012). Baseline risk factors were included in a multivariate logistic regression to determine their association with the development of constipation. To allow causal implications, nursing home residents with constipation at baseline were excluded. The variables examined included medications, mobility, comorbid illness, and nutrition., Results: The mean age (+/- standard deviation) of nursing home residents was 83 +/- 8 years, and the population was 70 percent female and 83 percent white. At baseline, the prevalence of constipation was 12.5 percent (N = 2,627). By the three-month assessment, 7 percent (N = 1,291) of nursing home residents had developed constipation. The factors associated independently with the development of constipation were, in order of magnitude, race, decreased fluid intake, pneumonia, Parkinson's disease, and the presence of allergies. Congestive heart failure and the use of a feeding tube were two factors identified as having a protective effect., Conclusion: The variables associated with the development of constipation may be used to identify geriatric nursing home residents at risk and to prevent constipation and its potential complications. Further study is needed to demonstrate a causal relationship between the risk factors and the development of constipation.

Bone mineral density (BMD) has been shown to predict fracture risk in community-dwelling older persons; however, no comparable prospective study has been performed in the long-term care setting where the role of BMD testing is uncertain. To determine the ability of a single BMD measurement to predict the risk of subsequent fracture in long-term care residents, we designed a prospective study in a 725-bed long-term care facility. A total of 252 Caucasian nursing home residents (mean age 88 years, 74% women) were recruited between 1992 and 1998. BMD of the hip, radius or both sites was measured using dual-energy X-ray absorptiometry. Participants were followed through September 1999 for the occurrence of fracture. Cox proportional hazards regression models were constructed to determine the relationship between BMD and the risk of fracture controlling for potentially confounding variables. Sixty-three incident osteoporotic fractures occurred during a median follow-up time of 2.3 years. The multivariate-adjusted risk of fracture for each standard deviation decrease in BMD was 2.82 (95% CI 1.81-4.42) at the total hip, 2.79 (95% CI 1.69-4.61) at the femoral neck, 2.26 (95% CI 1.51-3.38) at the trochanter, 1.83 (95% CI 1.14-2.94) at the radial shaft and 1.84 (95% CI 1.21-2.80) at the ultradistal radius. Subjects in the lowest age-specific quartile of femoral neck BMD had over 4 times the incidence of fracture compared with those in the highest quartile. BMD at either hip or radius was a predictor of osteoporotic fracture, although in women, radial BMD did not predict fracture. Knowledge of BMD in long-term care residents provides important information on subsequent fracture risk.

Objective: To examine the gender-specific association between characteristics in established long-term care residents and 1-year risk of mortality., Design: A retrospective cohort study., Setting: The Hebrew Rehabilitation Center for Aged, a 725-bed long-term care facility in Boston, Massachusetts. The 778 participants included 188 men (24%) and 590 women (76%)., Measurements: Minimum Data Set (MDS) information, including items from the following sections: cognition, communication, psychosocial, functional, diseases, health conditions and medication use., Results: Survival curves were significantly different for men and women (log rank test, P = 0.004). Based on proportional hazards analyses, increased age, (RR(m)=1.07, RR(w)=1.05), functional impairment (RR(m)=1.07, RR(w)=1.04), and weight loss (RR(m)=2.03, RR(w)=2.24) were associated with increased mortality in men and women. Additionally, shortness of breath (RR = 2.87) and lower body mass index (RR = 2.25) were associated with higher mortality in men, and diabetes (RR = 2.42), pressure ulcers (RR = 1.99), anemia (RR = 1.98), congestive heart failure (RR = 1.87), and a recent fall (RR = 1.88) were associated with higher mortality in women., Conclusions: Characteristics associated with 1-year mortality differ between men and women. These readily available data could be useful in making medical decisions and advance directives planning. Furthermore, these data may be beneficial in developing quality improvement initiatives and mortality prediction modeling.

Objective: To develop a condition-specific measure for assessing the impact of urge urinary incontinence (UI) on the quality of life (QoL) of older persons., Design: A 32-item Urge Impact Scale (URIS) was drafted using content area data from focus groups composed of urge incontinent older persons. Pilot testing in 21 urge incontinent persons (mean age 67.7 years) resulted in the elimination of eight items by internal consistency, skew, and patient response criteria. The resulting scale (URIS-24) was tested for reliability (internal consistency and test-retest correlation) and construct validity (correlation with UI severity from voiding records) in a separate group of 27 urge incontinent persons (89% women, mean age 72 years). Factor analysis of URIS-24 data from the combined 48 persons was used to explore the conceptual structure underlying urge UI-related QoL., Setting: University-affiliated community-based practice and tertiary hospital., Participants: Community-dwelling women and men, older than age 60 and with urge incontinence at least twice weekly, recruited from newspaper, newsletter, and radio advertisements., Results: Cronbach's alpha for URIS-32 was 0.84, and for URIS-24 it was 0.94. When administered (mean +/- standard deviation) 9.2 +/- 5.1 days apart, URIS-24 had good test-retest reliability for total scores (interclass coefficient = .88, concordance coefficient = .88), and individual item scores at time 2 were within 1 point (on a 5-category Likert scale) of time 1 answers for 89% of responses. URIS-24 scores had modest but nearly significant correlation with the number of UI episodes (r = -0.39, P = .05). Factor analysis revealed a three component structure corresponding to psychological burden, perception of personal control, and self concept., Conclusions: The URIS-24 is an internally-consistent, highly reproducible tool for the assessment of the QoL impact of urge UI on older persons. It can be used to evaluate QoL impact by specific items as well as by overall score. Compared with other UI-specific QoL measures, the URIS-24 had similar or superior internal consistency, test-retest reliability, and validity, but it is the first measure designed and tested specifically for older persons with urge UI. These results also highlight the multifactorial structure of urge UI-related QoL and the importance of its psychological dimensions.

Both age and gender influence cardiovascular autonomic control, which in turn may influence the ability to withstand adverse cardiac events and respond to orthostatic stress. The purpose of this study was (1) to quantify age- and gender- related alterations in autonomic control of blood pressure (BP) and (2) to examine the impact of these autonomic alterations on BP response to orthostatic stress. We measured continuous BP and R-R intervals and vasoactive peptide levels in the supine and 60 degrees head-up tilt positions during paced respiration (0.25 Hz) in 89 carefully screened healthy subjects (41 men, 48 women, aged 20 to 83 years). Data were analyzed by gender (age adjusted) and by age group (gender adjusted). During tilt, women had greater decreases in systolic BP than men (-10.2+/-2 versus -1.2+/-3 mm Hg; P=0.02) and smaller increases in low-frequency (sympathetically mediated) BP power (P=0.02). Upright plasma norepinephrine was lower in women (P=0.02). Women had greater supine high-frequency R-R interval power than men (P=0.0001). In elderly subjects, the tilt-induced increase in low-frequency BP power was also diminished (P=0.01), despite higher supine (P=0.02) and similar upright norepinephrine levels compared with younger subjects. Thus, healthy women have less sympathetic influence on BP and greater parasympathetic influence on R-R interval than men. Elderly subjects also have reduced sympathetic influence on BP, but this appears to be more consistent with a reduction in vasomotor sympathetic responsiveness.

Background: Atrial natriuretic peptide (ANP) levels are elevated in symptomatic heart failure and correlate with invasively measured left heart pressures., Objective: To examine the association between plasma ANP level and the subsequent development of congestive heart failure (CHF) in older subjects with no history of CHF., Design: A 7-year, prospective, blinded, cohort study., Setting: A life care facility in Boston, Massachusetts., Participants: Two hundred fifty-six frail older subjects (mean age 88 +/- 7) with no history of CHF at study entry., Main Outcome Measure: Clinical episodes of CHF with confirmatory chest roentgenogram findings. Cox proportional hazard analyses were performed to examine the relationship between ANP levels and the development of CHF while controlling for 19 clinical, physical, and laboratory parameters. A Kaplan-Meier estimator (log-rank test) was used to determine if the development of CHF differed by tertile of ANP., Results: During the follow-up period, 32% of the cohort developed CHF. The mean ANP level in the CHF group was 95 pmol/L +/- 11 pmol/L versus 60 pmol/L +/- 5 pmol/L in the no CHF group (two tailed t test P = .005). On multivariate analysis, a high ANP level was found to be associated significantly (P = .01) with the development of CHF., Conclusions: There is a statistically significant association between ANP level and the subsequent development of CHF in frail older individuals with no history of CHF.

To investigate the hypothesis that elevated serum anticholinergic activity is independently associated with delirium in ill elderly persons, the authors performed a cross-sectional study of 67 acutely ill older medical inpatients. The presence of delirium was evaluated with the Confusion Assessment Method, and the presence of many delirium symptoms was measured by the Delirium Symptom Interview. Demographic data and clinical characteristics that may be important for the development of delirium were also collected. Logistic regression techniques demonstrated that elevated serum anticholinergic activity was independently associated with delirium. Among the subjects with delirium, a greater number of delirium symptoms was associated with higher serum anticholinergic activity.

Objective: Determining prognosis is an important part of medical planning for long-term care residents. Clarifying the resident characteristics associated with increased mortality has received little attention from investigators, and many approaches that have been suggested are unsuitable for widespread use. Using a readily available database, we sought to determine factors associated with 1-year mortality in established long-term care residents., Design: A retrospective cohort study., Setting: A 725-bed long-term care facility., Measurements: We examined Minimum Data Set (MDS) information on 780 residents from April 1994 through August 1997. The association between death and 65 resident factors, covering a broad array of physical, functional, medical, and psychosocial measures, was examined initially in bivariate proportional hazards models. Putative factors with P values < .10 in bivariate analysis were considered in the multivariate analysis. Using these factors, we employed a forward step-wise multivariate proportional hazards regression method to select the set of factors associated independently with mortality at a P value < .05. A mortality score was developed by assigning points to each factor based on the risk ratio in the multivariate proportional hazards model. The performance characteristics of the model were examined using logistic regression., Results: Forty-four of the 65 factors examined were associated with 1-year mortality in bivariate proportional hazards analysis. Eight of these 44 factors were associated with 1-year mortality in the multivariate proportional hazards regression. These factors were functional impairment, weight loss, shortness of breath, male gender, low body mass index, swallowing problems, congestive heart failure, and advanced age. A higher mortality score was associated with a higher death rate in the subsequent year. The model demonstrated good performance with an area under the ROC curve of 0.77., Conclusions: Using a widely available database that requires no additional medical testing or staff training, a useful model for identifying factors associated with 1-year mortality in established long-term care residents can be developed. Widespread use of such a practical approach to assess mortality risk could be of benefit to patients, their families, and physicians for informing care plan decisions.

Background: There is a lack of prognostic data regarding tube feeding of institutionalized elderly people. The objective of this study was to determine the impact of feeding tubes on the survival of nursing home residents with chewing and swallowing problems, and to follow the course of the tube-fed residents over one year., Methods: We conducted a cohort study with 12-month follow-up using Minimum Data Set resident assessments from 1991. Participants included 5,266 nursing home residents over the age of 65 with chewing and swallowing problems living in 272 Washington state nursing homes. Residents who had a feeding tube were identified. Baseline clinical characteristics and 12-month survival were compared for residents with and without feeding tubes. The proportion of tube-fed residents who became tube-free during the follow-up period was determined, and clinical features that predicted this outcome were examined., Results: Among the residents with chewing and swallowing problems, 10.5% had a feeding tube. After adjusting for potential confounding covariates, tube-fed residents had a significantly higher one-year mortality rate than those without feeding tubes (risk ratio, 1.44; 95% CI, 1.17-1.76). Of the 430 residents with feeding tubes who survived the follow-up period, 25.1% became free of a feeding tube. Age less than 87 years was associated with a significantly greater likelihood of becoming tube-free (odds ratio, 1.66; 95% CI, 1.03-2.6)., Conclusions: Residents selected for feeding tube placement have poorer survival after one year than residents who are not tube-fed. However, the feeding tubes are removed in a significant proportion of residents who survive one year. Residents with a potentially reversible condition, for whom the feeding tubes are a temporary intervention, need to be identified.

Objectives: To develop a fall risk model that can be used to identify prospectively nursing home residents at risk for falling. The secondary objective was to determine whether the nursing home environment independently influenced the development of falls., Design: A prospective study involving 1 year of follow-up., Setting: Two hundred seventy-two nursing homes in the state of Washington., Participants: A total of 18,855 residents who had a baseline assessment in 1991 and a follow-up assessment within the subsequent year., Measurements: Baseline Minimum Data Set items that could be potential risk factors for falling were considered as independent variables. The dependent variable was whether the resident fell as reported at the follow-up assessment. We estimated the extrinsic risk attributable to particular nursing home environments by calculating the annual fall rate in each nursing home and grouping them into tertiles of fall risk according to these rates., Results: Factors associated independently with falling were fall history, wandering behavior, use of a cane or walker, deterioration of activities of daily living performance, age greater than 87 years, unsteady gait, transfer independence, wheelchair independence, and male gender. Nursing home residents with a fall history were more than three times as likely to fall during the follow-up period than residents without a fall history. Residents in homes with the highest tertile of fall rates were more than twice as likely to fall compared with residents of homes in the lowest tertile, independent of resident-specific risk factors., Conclusions: Fall history was identified as the strongest risk factor associated with subsequent falls and accounted for the vast majority of the predictive strength of the model. We recommend that fall history be used as an initial screener for determining eligibility for fall intervention efforts. Studies are needed to determine the facility characteristics that contribute to fall risk, independent of resident-specific risk factors.

Objectives: To determine if atrial natriuretic peptide (ANP) level is associated with mortality in the oldest old and to develop a comprehensive model of mortality in the oldest old using clinical and laboratory parameters., Design: Prospective cohort study with 7 years of follow-up., Setting: A 725-bed life care facility., Participants: 282 frail older individuals (mean age 88, range 70-102)., Measurements: Variables measured included age, gender, Charlson Comorbidity Index, functional measurements, weight, blood pressure, and multiple laboratory variables, including ANP. Main outcome measurement was death., Results: Eighty-four percent (237/282) of subjects died during the 7-year follow-up period. On univariate analysis, the risk ratio (RR) for ANP tertile was 1.28. On bivariate analysis, adjusting for the development of congestive heart failure, the RR was 1.22. On multivariate analysis, the following variables were associated with mortality: ANP tertile (RR 1.24), age (RR 1.04), female gender (RR 0.43), Charlson Comorbidity Index score (RR 1.13), mentation score (RR 1.27), BUN/Cr ratio (RR 1.04), albumin level (RR 0.63), and hemoglobin level (RR 0.84)., Conclusions: ANP level and other variables are independent risk factors for mortality in frail individuals. ANP level may indicate homeostatic failure to adapt to fluid volume changes or may reflect subclinical heart disease. ANP level contributes to a multivariate model of mortality in frail older individuals.

Objectives: To examine how functional status among older community-dwelling residents differs over time between those with and those without specific medical conditions., Design: Prospective cohort study., Participants: A total of 1060 community-dwelling Massachusetts residents aged 65 or older who were not totally functionally dependent at baseline assessment., Measurements: Functional status, five medical conditions (heart problem, arthritis, diabetes, cancer, and stroke), and the total number of these five medical conditions. Assessments were done at baseline and at two annual follow-ups., Results: Adjusted repeated measures analysis of covariance revealed a time difference (P < .001) for all five medical conditions and group differences for diabetes (P = .006) and stroke (P < .001). Functional abilities declined over time and those with specific medical conditions were more impaired initially, but the rate of decline did not significantly differ from those free of the condition. The presence of each additional medical condition resulted in additional impairment (P < .001), but the rate of decline over time did not differ by number of medical conditions., Conclusions: Efforts to reduce or prevent the development of specific medical conditions are essential to maintaining functional independence of older people as well as to reducing use of supportive services and admission rates to nursing homes. Particular attention should be directed toward preventing stroke since its consequences are the most functionally disabling.

Background: Orthostatic hypotension is a dangerous problem in elderly patients, often exacerbated by vasodilator medications. Age- and disease-related impairments in cardioacceleration and diastolic ventricular function may make older patients particularly vulnerable to the hypotensive effects of these drugs. Therefore we aimed to determine mechanisms of postural blood pressure regulation in elderly patients with coronary artery disease and to compare the effects of isosorbide dinitrate and nicardipine hydrochloride on postural blood pressure homeostasis in these patients., Methods: Twenty elderly subjects with stable coronary artery disease (age, 76 +/- 4 [SD] years) underwent a baseline evaluation followed by a double-blind, randomized crossover comparison of nicardipine (20 mg by mouth t.i.d.) versus isosorbide (20 mg by mouth t.i.d.). Doppler echocardiography and a 15-minute 60-degree head-up tilt test were conducted on no study medications and then after successive 3-week treatment periods with nicardipine or isosorbide. Blood pressure, heart rate, vascular resistance, cardiac output, and spectral characteristics of heart rate and blood pressure variability were measured before and during each tilt., Results: Isosorbide treatment was associated with a higher prevalence of symptoms of cerebral hypoperfusion and a failure to increase systemic vascular resistance during tilt. While taking isosorbide subjects were able to preserve cardiac output and maintain upright blood pressure through enhanced cardioacceleration. During nicardipine treatment systemic vascular resistance and low-frequency blood pressure variability were reduced, but the ability to increase systemic vascular resistance during tilt was preserved., Conclusions: Although nicardipine may decrease vascular responsiveness to sympathetic activation, the baroreflex-mediated vasoconstrictor response to upright tilt remains intact. In contrast, isosorbide impairs the systemic vascular response to orthostatic stress in elderly patients with stable coronary artery disease.

Objective: To determine the epidemiology, clinical characteristics and natural history of nursing home residents with a diagnosis of Parkinson's disease (PD)., Design: A cohort study with 18-month follow-up utilizing resident assessments from the National HealthCorp 1991-1992 dataset., Setting: Seventy-one National HealthCorp nursing homes., Participants: A total of 5020 nursing home residents older than age 55 were studied. Residents with primary and secondary diagnoses of PD were identified from the population using the International Classification of Diseases, Ninth Revision, Clinical Modification code 332.0., Measurements: Baseline demographic and clinical characteristics were compared for residents with and those without Parkinson's disease. Outcome measures over the course of 18 months included death and functional status., Results: The prevalence of a diagnosis of PD was 6.8%. Significant factors associated independently with PD included: younger age (79 +/- 7 vs 81 +/- 9 years; P < .001), male sex (32% vs 23%; P < .001), severe dependence in activities of daily living (OR = 1.26; 95% CI 1.08-1.46), impared body control (OR = 1.38; 95% CI 1.03-1.68), symptoms of depression (OR = 1.29; 95% CI 1.02-1.64), and the number of daily medications (OR = 1.23; 95% CI 1.08-1.44). Residents with a diagnosis of PD had a faster rate of functional decline over 18 months (P < .001) but did not have a higher mortality rate than residents without PD., Conclusions: Parkinson's disease is a relatively common diagnosis among nursing home residents and is associated with increased functional disability. There are several potentially modifiable conditions associated with PD that may offer an opportunity to design specific interventions and health services to improve the quality of life and slow functional decline in this frail population.

Recent data showing gender differences in autonomic control of heart rate and acute estrogen effects on vasodilatation suggest that estrogen may influence autonomic regulation of heart rate and blood pressure. We aimed to determine the effect of postmenopausal estrogen replacement therapy on autonomic control of beat-to-beat heart rate and blood pressure dynamics. Subjects included 20 healthy postmenopausal women aged 60 to 75 years with normal exercise tolerance tests, 10 of whom were taking oral estrogen for 13 +/- 3 (+/- SEM) years. Six healthy premenopausal women were also studied. Continuous electrocardiographic and noninvasive radial artery blood pressure measurements and intermittent forearm blood flow recordings (by venous-occlusion plethysmography) were obtained before and after a 20-minute, 60 degrees head-up tilt and a 420-kcal meal during periods of spontaneous and metronomic breathing (at 0.25 Hz). Low-frequency (0.01- to 0.15-Hz) and high-frequency (0.15- to 0.50-Hz) heart rate and blood pressure spectral powers were compared with a fast Fourier transform. Cardiovascular and heart rate spectral power responses to upright tilt and meal digestion were the same in postmenopausal estrogen users and nonusers. However, during spontaneous breathing the blood pressure spectral power responses to upright tilt and meal ingestion were significantly different between the two groups of women. The low-frequency systolic pressure power response to upright tilt was smaller in estrogen users than nonusers (P = .01). After meal ingestion nonusers had an early postprandial fall (20 to 30 minutes after the meal) and late rise (50 to 60 minutes) in low-frequency systolic and diastolic pressure powers, which were significantly attenuated in estrogen users (P < .02).(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To determine whether differences in genetic origin affect the clinical course of Alzheimer's disease (AD). The limited number of cases of AD linked to a known genetic abnormality is a major obstacle in determining whether the disorder is expressed differently in patients with familial AD and those with sporadic AD., Design: Cross-sectional study., Setting: Memory Disorders Unit of the Alzheimer's Disease Research Center at Massachusetts General Hospital, Boston., Participants: A total of 186 patients who had a clinical diagnosis of probable AD, family history information available for all first-degree relatives, and three or more outpatient visits were identified from a consecutive case series., Main Outcome Measures: Rate of decline on the Blessed Dementia Scale and the Activities of Daily Living Scale., Results: We calculated the probability that an individual patient has a major genetic locus for AD (MGAD) using an algorithm that incorporates information from a genetic model and the individual's family. We measured cognitive and functional changes by the average annual rate of increase (slope) in scores for the Blessed Dementia Scale and Activities of Daily Living Scale, respectively. Multivariate analysis adjusted for age at onset, duration of illness at entry into the study, and education level indicated that scores on the Activities of Daily Living Scale worsened significantly faster in men with MGAD than in men with non-MGAD. No differences in Activities of Daily Living Scale slopes were observed among women with MGAD and non-MGAD. The slopes for Blessed Dementia Scale scores were similar in men and women regardless of the MGAD probability., Conclusions: Genetic factors may account for heterogeneity in rates of functional decline in AD. This study also illustrates the practical application of a probabilistic method that characterizes the genetic status of AD in an individual patient.

The authors prospectively examined the influence of increased levels of physical activity on risk of stroke in members of the Framingham Study cohort. Two separate analyses were performed, one during midlife in 1,897 men (mean age = 49.7 years) and 2,299 women (mean age = 49.9 years) and another when the cohort was older (1,361 men (mean age = 63.0) and 1,862 women (mean age = 63.7)). A structured questionnaire administered at two separate examinations was used to estimate the amount of metabolic work done during a typical 24-hour period. Physical activity was categorized into tertiles, and medium and high levels of physical activity were compared with a low level of physical activity, which was used as the referent group. Cox proportional hazards, life table, and time-dependent covariate analyses were used to examine the relation between level of physical activity and stroke risk over a follow-up period of up to 32 years. In men, adjusted analyses revealed that increased levels of physical activity were protective. The strongest effect was obtained from an analysis involving older cohort members in the medium tertile (risk ratio = 0.41, 95% confidence interval 0.24-0.69). High levels of physical activity did not confer an additional benefit over medium levels. Adjusted analyses showed no significant protective effect in women. These results indicate that medium and high levels of physical activity among men are protective against stroke relative to low levels.

There are standardized criteria to assist in the diagnosis of Alzheimer's disease (AD), a disorder that lacks unique clinical, morphologic, or biochemical features. Diagnostic reliability of single groups of investigators using these criteria is moderate to substantial. In this study, seven clinicians at separate sites established a criteria-based diagnosis in 42 consecutive memory disorder patients participating in a national genetic epidemiologic study using a quantitative multiaxis AD rating scale (ADRS) that incorporates NINCDS/ADRDA criteria, reliability of information, and comorbidity. Reliability, measured by a generalized kappa statistic for more than two raters, was substantial (0.63 +/- 0.13) when the subjects were grouped as "AD" (probable or possible) versus "not AD," but somewhat lower (0.52 +/- 0.10) when subjects were classified as probable AD, possible AD, or not AD. There was unanimous agreement for two-thirds of the subjects using a dichotomous classification scheme. These findings suggest that the ADRS is a useful diagnostic instrument for multicenter studies.

Background and Purpose: Family history is perceived to be an important risk factor for stroke despite conflicting published data. We examined patterns of familial aggregation of stroke among three generations using data from the Framingham Study., Methods: Cox proportional hazards analyses, adjusting for known stroke risk factors, were used to examine familial concordance in three groups: (1) members of the original Framingham cohort using reported parental stroke death; (2) members of the Framingham Offspring Study and their parents (members of the original Framingham Study); and (3) sibships within the original Framingham cohort., Results: We found no association between stroke or transient ischemic attack among original cohort members and their reported parental stroke death (n = 4933; relative risk [RR] = 1.07). Using verified cases of parental stroke or transient ischemic attack, the Offspring analyses revealed that both paternal (n = 1762; RR = 2.4; 95% confidence interval [CI], 0.96 to 6.03) and maternal (n = 2074; RR = 1.4; 95% CI, 0.60 to 3.25) histories were associated with an increased risk. Parental history of coronary heart disease was strongly associated with stroke or transient ischemic attack among Offspring Study members (RR = 3.33; 95% CI, 1.27 to 8.72). Sibling history of stroke or transient ischemic attack was not associated with stroke or transient ischemic attack among original cohort members, although a non-statistically significant increased risk associated with sibling history of atherothrombotic brain infarction was observed (RR = 1.8; 95% CI, 0.68 to 4.94)., Conclusions: These analyses suggest that parental history of stroke may be a risk factor for stroke. As more stroke or transient ischemic attack events develop among the Offspring Study members, it will be valuable to reexamine these associations.

It is well recognized that age at onset of Huntington disease (HD) is strongly influenced by the sex of the affected parent, and this has lead to suggestions that genetic imprinting or maternal specific factors may play a role in the expression of the disease. This study evaluated maternal and paternal ages, birth order, parental age at onset, and sex of the affected parent and grandparent in 1,764 patients in the National HD Roster by using linear-regression techniques which incorporated a weighted least-squares approach to accommodate the correlation among siblings. It was found that paternal age is negatively associated with age at onset of HD, particularly among subjects who inherit the mutant gene from grandfathers. Apparent associations between age at onset and birth order and between age at onset and maternal age were not significant after adjustment for paternal age. The paternal age effect is strongest among juvenile-onset cases and individuals with anticipation of greater than or equal to 10 years, although it is detectable across the entire age-at-onset distribution. The tendency for older fathers, including those not transmitting the HD gene, to have affected offspring with early-onset disease may be consistent with a gene imprinting mechanism involving DNA methylation. Because paternal age in unaffected fathers is also a significant determinant of age at onset, methylation in this context might involve HD modifier genes or the normal HD allele.

Family patterns for age at death were examined in a 40 year follow-up of 5209 men and women (2900 deceased, 2309 living) in the Framingham Study and their parents. Age at death of both mothers and fathers was significantly older for surviving offspring when compared to decreased offspring (p less than 0.0001). When longevity was assessed according to cause of death in the offspring, parental age at death was a significant predictor of death by coronary heart disease (CHD), but not for stroke or cancer. Multiple regression analysis for offspring with sudden CHD death revealed that mother's age at death was a significant predictor of age at sudden CHD death (p less than 0.0003) whereas father's age at death was a significant predictor of age at death in non-sudden CHD death (p less than 0.004). Life table analysis showed longest survival rates associated with both parents surviving to age 75 or older followed by mother only surviving to age 75 or older, then father only, and shortest survival with neither parent surviving to age 75. Longevity appears to be more strongly associated with maternal death age than parental death age. Proportional hazards analysis of risk factors associated with CHD revealed that systolic blood pressure, sex of the individual, and cigarette smoking were the most significant predictors of death age. These findings suggest that familial similarities for death age may be mediated primarily through shared CHD risk factors within families, either genetic or non-genetic.

Decreased density of neurons was found throughout the head of the caudate nucleus in Huntington's disease (HD), with the most severe neuronal loss early in the disease in the medial region. The density of reactive astrocytes is inversely proportional to the neuronal loss. In cases of mild Huntington's disease which had no identifiable abnormality on conventional neuropathologic evaluation (grade 0), there is a reduction in neuron density without an accompanying reactive astrocytosis. The pattern for decrease in neurons and accompanying astrocytosis suggests that the earliest changes occur in the most medial portion of the head of the caudate nucleus and subsequently sweep laterally across the caudate nucleus to the internal capsule. An increased density of oligodendrocytes is observed in the head of the caudate nucleus for the lower grades (0, 1 and 2). The decreased neuronal and increased oligodendroglial densities may be of significance in understanding the pathogenesis of HD. These altered densities, observed in the absence of reactive astrocytosis, suggest that these changes may not represent recent effects of disease, but rather that HD gene expression may influence brain cell densities from early in the life of the gene carrier.

The rate of disease progression was assessed for 42 persons affected by Huntington's disease who had been neurologically examined at least six times and followed up for at least 3 years. Disease progression was assessed by a disability rating scale administered at each examination. Slow progression was associated with older age at onset of disease and with heavier weight (body mass index) at the first examination. Men tended to have a slower disease progression than did women, and this was particularly evident among men inheriting Huntington's disease from affected mothers. Neither the butyrophenone haloperidol nor the tricyclic antidepressant imipramine were related to rate of progression. Assessments of depression, hostility, and tobacco use were also unrelated to rate of progression. Clinical trials in Huntington's disease should consider these factors when designing therapeutic studies.

We performed a morphometric analysis of cresyl violet-stained sections from the dorsolateral prefrontal cortex of 81 patients with Huntington's disease (HD) (grades 2, 3, and 4) and 23 age-matched normal controls. We counted large pyramidal neurons, small neurons, astrocytes, oligodendroglia, and microglia under the guidance of a specifically predefined set of morphologic criteria for each cell type and recorded the thickness of each cortical layer. Our results demonstrate a selective and progressive loss of a subset of the large pyramidal neurons in cortical layers III, V, and VI of HD patients, and a decrease in the thickness of the respective cortical laminae. A genetically determined, cell-autonomous degeneration of cortical neurons could constitute the primary pathologic process. However, the loss of only a fraction of pyramidal cells suggest a parallel, or an alternative, possibility of a retrograde degeneration of cortical neurons that project solely, or principally, to the site of primary degeneration in caudate nuclei.

The predictive test for Huntington disease (HD) has allowed those at risk to determine gene status prior to symptoms. The purpose of this research was to understand the motivation and the anticipated reactions of those requesting the test. Forty persons at 50% risk for HD and 31 companions participated in a structured personal interview as part of the predictive test protocol. Reasons for taking the test centered on the reduction of anxiety and uncertainty associated with being at risk and enhanced planning and decision making. Participants also believed that taking the test would produce more positive than negative outcomes. With a favorable result, most anticipated a reduction of anxiety, a more normal future, and relief knowing their children would be at a very low risk. Most also cited benefits as more likely than consequences with an unfavorable result. Making the most of life, easier planning, and reduced uncertainty were rated as more likely than any of the adverse impacts, including short-term depression and becoming frightened. Almost all participants (95%) said they would rather learn that they have the HD gene than remain at 50% risk. The uncertainty, anxiety, and chronic stress associated with being at risk appears to underlie the motivation of many seeking the predictive test for HD.

Family history of CAD, defined as parental death by CAD, was found to be a significant independent predictor of CAD in a logistic regression model controlling for standard risk factors and length of follow-up among the 5209 participants in the Framingham Study. Persons with a positive parental history have a 29% increased risk of CAD, and the strength of the association between parental history and CAD is similar to that found for other standard risk factors such as systolic blood pressure, cholesterol level, and cigarette smoking. No evidence was found that persons with a family history of CAD have a decreased capacity to cope with the deleterious effects of known risk factors; that is, no significant interaction was found between any of the risk factors and parental history of CAD. Among men with low risk for CAD by risk-factor profile (i.e., nonsmoking, thin, nonhypertensive persons), more than two thirds of those who experience CAD have a positive parental history. This study suggests that CAD among persons who are predicted to be at low risk by standard risk factors may have a substantial genetic component and that the risk associated with parental history may not be reduced by modification of these factors. Nevertheless, among persons with a positive family history, those with a favorable risk profile are at substantially less risk for CAD than those with an unfavorable risk profile.

The advent of presymptomatic and prenatal testing in Huntington disease (HD) may change the reproductive behavior of persons at risk for HD. In order to assess future change, an analysis of fertility and reproductive fitness was carried out on 999 affected and 2,253 unaffected offspring from 235 New England families. Ascertainment biases observed for persons born before 1910 and after 1929 reduced the sample to 250 HD cases and 201 unaffected sib controls born between 1910 and 1929. No increase in reproductive rate was found in HD-affected men compared to male control sibs. A small increase in fertility averaging 0.5 child was seen in HD-affected females compared to unaffected females, but this difference was not significant. The increase in mean number of children for HD females is accounted for in part by a small number of affected women who had very large families. No evidence was found to suggest that any increase in reproductive rate for affected persons was related to offspring being born after HD onset. The fitness of both HD-affected and unaffected females was not significantly different from that of the general population of Massachusetts.

Data from the Framingham Study, a population-based prospective study of 5,209 persons, were analyzed to determine whether a parental history of death by coronary artery disease (CAD) before or after 65 years of age was an independent risk factor for CAD of early onset (age younger than 60 years) or late onset (age 60 years or older) among the men and women in the cohort. Death due to CAD in parents was associated with a 30% increase in the risk of CAD. The effect was apparently stronger for an early CAD outcome, with adjusted relative risks of 1.5 for early and 1.2 for late outcome CAD. The effect of parental CAD death on risk was not mediated by other shared risk factors for CAD. These findings were similar for those with either a mother or a father with CAD, if CAD onset in the offspring occurred before the age of 60 years. For persons with CAD at age 60 years or older, maternal CAD death was a stronger predictor of CAD than paternal CAD death. The association with parental history of CAD was similar among men and women in the cohort, with adjusted relative risks of 1.3 and 1.2, respectively. However, early age of parental CAD death may account for the association among women (RR = 1.6), whereas late age of CAD death for either parent was associated with the risk of CAD among men (RR = 1.4).