@article {897, title = {The Cardiovascular Health Study: design and rationale.}, journal = {Ann Epidemiol}, volume = {1}, year = {1991}, month = {1991 Feb}, pages = {263-76}, abstract = {

The Cardiovascular Health Study (CHS) is a population-based, longitudinal study of coronary heart disease and stroke in adults aged 65 years and older. The main objective of the study is to identify factors related to the onset and course of coronary heart disease and stroke. CHS is designed to determine the importance of conventional cardiovascular disease (CVD) risk factors in older adults, and to identify new risk factors in this age group, especially those that may be protective and modifiable. The study design called for enrollment of 1250 men and women in each of four communities: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania. Eligible participants were sampled from Medicare eligibility lists in each area. Extensive physical and laboratory evaluations were performed at baseline to identify the presence and severity of CVD risk factors such as hypertension, hypercholesterolemia and glucose intolerance; subclinical disease such as carotid artery atherosclerosis, left ventricular enlargement, and transient ischemia; and clinically overt CVD. These examinations in CHS permit evaluation of CVD risk factors in older adults, particularly in groups previously under-represented in epidemiologic studies, such as women and the very old. The first of two examination cycles began in June 1989. A second comprehensive examination will be repeated three years later. Periodic interim contacts are scheduled to ascertain and verify the incidence of CVD events, the frequency of recurrent events, and the sequellae of CVD.

}, keywords = {Aged, Cerebrovascular Disorders, Coronary Disease, Epidemiologic Methods, Female, Health Status, Humans, Longitudinal Studies, Male, Physical Examination, Research Design, Risk Factors, United States}, issn = {1047-2797}, doi = {10.1016/1047-2797(91)90005-w}, author = {Fried, L P and Borhani, N O and Enright, P and Furberg, C D and Gardin, J M and Kronmal, R A and Kuller, L H and Manolio, T A and Mittelmark, M B and Newman, A} } @article {808, title = {Eligibility for cholesterol referral in community-dwelling older adults. The Cardiovascular Health Study.}, journal = {Ann Intern Med}, volume = {116}, year = {1992}, month = {1992 Apr 15}, pages = {641-9}, abstract = {

OBJECTIVES: To assess the proportion of community-dwelling adults aged 65 years or older who are eligible for referral for lipoprotein analysis and intervention according to the National Cholesterol Education Program (NCEP) guidelines.

DESIGN: Cross-sectional study based on examinations and questionnaires collected in 1989 and 1990.

SETTING: Four communities in the U.S. in the Cardiovascular Health Study (CHS), a study of risk factors for heart disease and stroke in older adults.

PARTICIPANTS: A sample of 4810 men and women ages 65 to 100 randomly selected and recruited from Health Care Financing Administration Medicare eligibility lists for the four communities; not institutionalized, not wheelchair-bound, not currently receiving therapy for cancer, not currently taking lipid-lowering medications, and not having eaten in the preceding 9 hours.

MEASUREMENTS: Total cholesterol and lipoprotein analysis measured in all participants.

RESULTS: Total cholesterol levels were less than 5.17 mmol/L (200 mg/dL) in 37\% of participants, 5.17 to 6.19 mmol/L (200 to 239 mg/dL) in 39\%, and 6.20 mmol/L (240 mg/dL) or greater in 24\%. Compared with their counterparts, older participants, especially those over 80 years of age, were more likely to have levels below 5.17 mmol/L, as were men, nonwhites, and those with coronary heart disease or two or more coronary heart disease risk factors (P less than 0.008 for all values). Based on this screening measurement, 2174 participants were eligible for lipoprotein analysis, 80\% were eligible for dietary or drug therapy using NCEP guidelines. Overall, 46\% of CHS participants were eligible for lipoprotein analysis and 36\% for intervention by NCEP guidelines, based on a single cholesterol measurement.

CONCLUSION: A substantial proportion of older adults in this community sample were eligible for lipoprotein analysis and intervention. Prospective studies of elderly persons are needed to determine the risk for incident coronary heart disease according to NCEP classifications and the benefits of lipid-lowering treatments in persons in this age group so that intervention strategies may best be targeted to an appropriately high-risk group.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Cerebrovascular Disorders, Cholesterol, LDL, Coronary Disease, Eligibility Determination, Female, Humans, Hypercholesterolemia, Longitudinal Studies, Male, Primary Prevention, Referral and Consultation, Risk Factors, United States}, issn = {0003-4819}, doi = {10.7326/0003-4819-116-8-641}, author = {Manolio, T A and Furberg, C D and Wahl, P W and Tracy, R P and Borhani, N O and Gardin, J M and Fried, L P and O{\textquoteright}Leary, D H and Kuller, L H} } @article {748, title = {Isolated systolic hypertension and subclinical cardiovascular disease in the elderly. Initial findings from the Cardiovascular Health Study.}, journal = {JAMA}, volume = {268}, year = {1992}, month = {1992 Sep 09}, pages = {1287-91}, abstract = {

OBJECTIVE: To assess the association between isolated systolic hypertension (ISH) and subclinical disease in adults aged 65 years and above.

DESIGN: Medicare eligibility lists were used to obtain a representative sample of 5201 community-dwelling elderly persons for the Cardiovascular Health Study, a National Heart, Lung, and Blood Institute--sponsored cohort study of risk factors for coronary heart disease and stroke. In this cross-sectional analysis of baseline data, we excluded 3012 participants who were receiving antihypertensive medications, had clinical cardiovascular disease, or had a diastolic blood pressure of at least 90 mm Hg.

MAIN OUTCOME MEASURES: For electrocardiogram: myocardial infarction, left ventricular hypertrophy, and left ventricular mass as measures of myocardial damage and strain; for echocardiography: left ventricular mass, fractional shortening, and Doppler flow velocities as measures of cardiac systolic and diastolic function; and for carotid sonography: carotid arterial intima-media thickness as a measure of atherosclerosis.

RESULTS: Among the 2189 men and women in this analysis, 195 (9\%) had ISH (systolic blood pressure, greater than or equal to 160 mm Hg) and 596 (23\%) had borderline ISH (systolic blood pressure, 140 to 159 mm Hg). Systolic blood pressure was associated with myocardial infarction by electrocardiogram (P = .02). Borderline and definite ISH were strongly associated with left ventricular mass (P less than .001). While there was little association with cardiac systolic function, borderline and definite ISH were associated with cardiac diastolic function (P less than .001). Isolated systolic hypertension was also strongly associated with increased intima-media thickness of the carotid artery (P less than .001).

CONCLUSIONS: While cohort analyses of future repeated measures will provide a better assessment of risk, both borderline and definite ISH were strongly related to a variety of measures of subclinical disease in elderly men and women.

}, keywords = {Aged, Aged, 80 and over, Cardiomegaly, Cardiovascular Diseases, Carotid Artery Diseases, Cerebrovascular Disorders, Coronary Disease, Cross-Sectional Studies, Echocardiography, Electrocardiography, Female, Humans, Hypertension, Male, Myocardial Infarction, Prospective Studies, Risk Factors, Systole}, issn = {0098-7484}, author = {Psaty, B M and Furberg, C D and Kuller, L H and Borhani, N O and Rautaharju, P M and O{\textquoteright}Leary, D H and Bild, D E and Robbins, J and Fried, L P and Reid, C} } @article {781, title = {Lipoprotein lipids in older people. Results from the Cardiovascular Health Study. The CHS Collaborative Research Group.}, journal = {Circulation}, volume = {86}, year = {1992}, month = {1992 Sep}, pages = {858-69}, abstract = {

BACKGROUND: Cardiovascular disease is the leading cause of death and disability in older people. There is little information about the distributions of risk factors in older populations. This article describes the distribution and correlates of lipoprotein lipids in people greater than or equal to 65 years old.

METHODS AND RESULTS: Lipoprotein lipid concentrations were measured in 2,106 men (M) and 2,732 women (F) who were participants in the Cardiovascular Health Study, a population-based epidemiological study. Distributions of lipids by age and sex and bivariate and multivariate relations among lipids and other variables were determined in cross-sectional analyses. Mean concentrations of lipids were cholesterol: M, 5.20 +/- 0.93 mmol/l (201 +/- 36 mg/dl) and F, 5.81 +/- 0.98 mmol/l (225 +/- 38 mg/dl); triglyceride (TG): M, 1.58 +/- 0.85 mmol/l (140 +/- 75 mg/dl) and F, 1.57 +/- 0.78 mmol/l (139 +/- 69 mg/dl); high density lipoprotein cholesterol (HDL-C): M, 1.23 +/- 0.33 mmol/l (48 +/- 16 mg/dl), and F, 1.53 +/- 0.41 mmol/l (59 +/- 16 mg/dl); low density lipoprotein cholesterol (LDL-C): M, 3.27 +/- 0.85 mmol/l (127 +/- 33 mg/dl) and F, 3.57 +/- 0.93 mmol/l (138 +/- 36 mg/dl). The total cholesterol to HDL-C ratios were M, 4.49 +/- 1.29 and F, 4.05 +/- 1.22. TG, total cholesterol, and LDL-C concentrations were lower with increasing age, the last more evident in men than in women. TG concentration was positively associated with obesity (in women), central fat patterning, glucose intolerance, use of beta-blockers (in men), and use of estrogens (in women) and negatively associated with age, renal function, alcohol use, and socioeconomic status. In general, HDL-C had opposite relations with these variables, except that estrogen use was associated with higher HDL-C concentrations. LDL-C concentration was associated with far fewer variables than the other lipids but was negatively associated with age in men and women and positively correlated with obesity and central fat patterning and negatively correlated with renal function and estrogen use in women. There were no differences in total cholesterol and LDL-C concentrations among participants with and without prevalent coronary heart disease and stroke, but TG concentration was higher and HDL-C lower in men with both coronary heart disease and stroke and in women with coronary heart disease.

CONCLUSIONS: Cholesterol and cholesterol/HDL-C ratio were lower and HDL-C higher than previously reported values in older people, suggesting that lipid risk profiles may be improving in older Americans. TG and HDL-C concentrations, and to a lesser extent LDL-C, were associated with potentially important modifiable factors such as obesity, glucose intolerance, renal function, and medication use.

}, keywords = {Aged, Aging, Cardiovascular Diseases, Cardiovascular Physiological Phenomena, Cholesterol, HDL, Cholesterol, LDL, Cross-Sectional Studies, Female, Health Status, Humans, Lipids, Lipoproteins, Male, Multivariate Analysis, Triglycerides}, issn = {0009-7322}, doi = {10.1161/01.cir.86.3.858}, author = {Ettinger, W H and Wahl, P W and Kuller, L H and Bush, T L and Tracy, R P and Manolio, T A and Borhani, N O and Wong, N D and O{\textquoteright}Leary, D H} } @article {1445, title = {Epidemiology of low cholesterol levels in older adults. The Cardiovascular Health Study.}, journal = {Circulation}, volume = {87}, year = {1993}, month = {1993 Mar}, pages = {728-37}, abstract = {

BACKGROUND: Low cholesterol levels have been associated with increased mortality from stroke, cancer, and other noncardiovascular diseases, but the reasons for this association remain unclear. One explanation is that persons with low cholesterol levels have early or occult disease that eventually leads to their deaths.

METHODS AND RESULTS: This possibility was explored in 2,091 men and 2,714 women 65-100 years old in the Cardiovascular Health Study, a multicenter observational study of risk factors for heart disease and stroke in older adults. Cholesterol levels < or = 160 mg/dL were present in 11.6\% of men and 3.7\% of women and increased in prevalence with age. After adjustment for age, total cholesterol levels in this range were associated with a twofold increased prevalence of treated diabetes in men and women and with a twofold increased prevalence of cancer diagnosed in the preceding 5 years in women only. Low cholesterol was also associated with lower levels of hemoglobin, albumin, and factor VII, suggesting a link with hepatic synthetic function. On multivariate analysis, factors most strongly associated with low cholesterol levels in men and women were decreased factor VII levels, decreased albumin, and diabetes.

CONCLUSIONS: Cross-sectional associations with low cholesterol levels differ by sex and suggest poorer health by some measures. The observed relations with treated diabetes and impaired hepatic synthetic function should be examined for risk of mortality in longitudinal data from this and other observational studies.

}, keywords = {Aged, Aged, 80 and over, Aging, Cardiovascular Diseases, Cardiovascular Physiological Phenomena, Cholesterol, Female, Health Status, Humans, Longitudinal Studies, Male, Prevalence, Probability, Regression Analysis, Risk Factors}, issn = {0009-7322}, author = {Manolio, T A and Ettinger, W H and Tracy, R P and Kuller, L H and Borhani, N O and Lynch, J C and Fried, L P} } @article {1449, title = {Methods of assessing prevalent cardiovascular disease in the Cardiovascular Health Study.}, journal = {Ann Epidemiol}, volume = {5}, year = {1995}, month = {1995 Jul}, pages = {270-7}, abstract = {

The objective of this article is to describe the methods of assessing cardiovascular conditions among older adults recruited to the Cardiovascular Health Study (CHS), a cohort study of risk factors for coronary disease and stroke. Medicare eligibility lists from four US communities were used to obtain a representative sample of 5201 community-dwelling elderly, who answered standardized questionnaires and underwent an extensive clinic examination at baseline. For each cardiovascular condition, self-reports were confirmed by components of the baseline examination or, if necessary, by a validation protocol that included either the review of medical records or surveys of treating physicians. Potential underreporting of a condition was detected either by the review of medical records at baseline for other self-reported conditions or, during prospective follow-up, by the investigation of potential incident events. For myocardial infarction, 75.5\% of the self-reports in men and 60.6\% in women were confirmed. Self-reported congestive heart failure was confirmed in 73.3\% of men and 76.6\% of women; stroke, in 59.6\% of men and 53.8\% of women; and transient ischemic attack, in 41.5\% of men and 37.0\% of women. Underreporting was also common. During prospective follow-up of an average of about 3 years per person, approximately 50\% of men and 38\% of women were hospitalized or investigated for at least one potential incident event; for each cardiovascular condition, about 1 to 4\% of those investigated during prospective follow-up were found to have had the cardiovascular condition prior to entry into the cohort.(ABSTRACT TRUNCATED AT 250 WORDS)

}, keywords = {Aged, Cerebrovascular Disorders, Cohort Studies, Coronary Disease, Electrocardiography, Epidemiologic Methods, False Negative Reactions, Female, Humans, Male, Population Surveillance, Prevalence, Prospective Studies, Reproducibility of Results, Risk Factors, Self Disclosure, United States}, issn = {1047-2797}, author = {Psaty, B M and Kuller, L H and Bild, D and Burke, G L and Kittner, S J and Mittelmark, M and Price, T R and Rautaharju, P M and Robbins, J} } @article {1415, title = {Subclinical disease as an independent risk factor for cardiovascular disease.}, journal = {Circulation}, volume = {92}, year = {1995}, month = {1995 Aug 15}, pages = {720-6}, abstract = {

BACKGROUND: The primary aim of the present study was to determine the relation between measures of subclinical cardiovascular disease and the incidence of clinical cardiovascular disease among 5201 adults 65 years of age or older who were participating in the Cardiovascular Health Study.

METHODS AND RESULTS: A new method of classifying subclinical disease at baseline examination in the Cardiovascular Health Study included measures of ankle-brachial blood pressure, carotid artery stenosis and wall thickness, ECG and echocardiographic abnormalities, and positive response to the Rose Angina and Claudication Questionnaire. Participants were followed for an average of 2.39 years (maximum, 3 years). For participants without evidence of clinical cardiovascular disease at baseline, the presence of subclinical disease compared with no subclinical disease was associated with a significant increased risk of incident total coronary heart disease including CHD deaths and nonfatal MI and angina pectoris for both men and women. For individuals with subclinical disease, the increased risk of total coronary heart disease was 2.0 for men and 2.5 for women, and the increased risk of total mortality was 2.9 for men and 1.7 for women. The increased risk changed little after adjustment for other risk factors, including lipoprotein levels, blood pressure, smoking, and diabetes.

CONCLUSIONS: The measurement of subclinical disease provides an approach for identifying high-risk older individuals who may be candidates for more active intervention to prevent clinical disease.

}, keywords = {Aged, Cardiovascular Diseases, Cohort Studies, Coronary Disease, Female, Humans, Incidence, Longitudinal Studies, Male, Myocardial Infarction, Odds Ratio, Reference Values, Risk Factors}, issn = {0009-7322}, author = {Kuller, L H and Shemanski, L and Psaty, B M and Borhani, N O and Gardin, J and Haan, M N and O{\textquoteright}Leary, D H and Savage, P J and Tell, G S and Tracy, R} } @article {1450, title = {Surveillance and ascertainment of cardiovascular events. The Cardiovascular Health Study.}, journal = {Ann Epidemiol}, volume = {5}, year = {1995}, month = {1995 Jul}, pages = {278-85}, abstract = {

While previous prospective multicenter studies have conducted cardiovascular disease surveillance, few have detailed the techniques relating to the ascertainment of and data collection for events. The Cardiovascular Health Study (CHS) is a population-based study of coronary heart disease and stroke in older adults. This article summarizes the CHS events protocol and describes the methods of surveillance and ascertainment of hospitalized and nonhospitalized events, the use of medical records and other support documents, organizational issues at the field center level, and the classification of events through an adjudication process. We present data on incidence and mortality, the classification of adjudicated events, and the agreement between classification by the Events Subcommittee and the medical records diagnostic codes. The CHS techniques are a successful model for complete ascertainment, investigation, and documentation of events in an older cohort.

}, keywords = {Aged, Cerebrovascular Disorders, Coronary Disease, Epidemiologic Methods, Female, Hospitalization, Humans, Incidence, Longitudinal Studies, Male, Population Surveillance, Quality Control, United States}, issn = {1047-2797}, author = {Ives, D G and Fitzpatrick, A L and Bild, D E and Psaty, B M and Kuller, L H and Crowley, P M and Cruise, R G and Theroux, S} } @article {1464, title = {Correlates of thrombin markers in an elderly cohort free of clinical cardiovascular disease.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {16}, year = {1996}, month = {1996 Sep}, pages = {1163-9}, abstract = {

Studies suggest that thrombosis is important in the progression of atherosclerotic lesions. The biochemical markers prothrombin fragment 1-2 and fibrinopeptide A reflect in vivo thrombin generation and activity, respectively. As such, they are markers that might be associated with cardiovascular risk. From the Cardiovascular Health Study, a cohort study of 5201 persons over 65 years of age, 399 persons free of clinical cardiovascular disease (CVD) at the baseline examination were selected for study of specialized markers of hemostasis. We report the cross-sectional relationships of the thrombin markers to CVD risk factors and measures of subclinical CVD. The range of fragment 1-2 2 was 0.12 to 0.85 nmol/L. The range of fibrinopeptide A was 0.9 to 44.1 micrograms/L. High levels of fragment 1-2 and fibrinopeptide A were associated with age, with levels higher in women than men. Fragment 1-2 was associated with smoking; high levels of triglyceride, creatinine, and C-reactive protein; and low levels of glucose. Fibrinopeptide A was associated with high C-reactive protein and apolipoprotein(a) and lower ankle-brachial index. There were no significant associations of the thrombin markers with race, fibrinogen, alcohol consumption, diabetes, or most measures of subclinical CVD. Study findings support a hypothesis that there are physiological interrelationships between cardiac risk factors, hemostasis, inflammation, and progression of atherosclerosis.

}, keywords = {Aged, Biomarkers, Cardiovascular Diseases, Cohort Studies, Female, Hemostasis, Humans, Male, Risk Factors, Thrombin}, issn = {1079-5642}, author = {Cushman, M and Psaty, B M and Macy, E and Bovill, E G and Cornell, E S and Kuller, L H and Tracy, R P} } @article {1459, title = {Risk factors for abdominal aortic aneurysms in older adults enrolled in The Cardiovascular Health Study.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {16}, year = {1996}, month = {1996 Aug}, pages = {963-70}, abstract = {

B-mode ultrasound examinations of the abdominal aorta were performed from 1990 to 1992 to evaluate the prevalence of abdominal aortic aneurysm (AAA) in a subgroup of the Pittsburgh cohort (656 participants, aged 65 to 90 years) of the Cardiovascular Health Study (CHS). In this pilot study, we evaluated various definitions of aneurysm and the reproducibility of the measurements. In year 5 (1992 to 1993) of the CHS, the entire cohort (4741 participants) was examined. AAA was defined as an infrarenal aortic diameter of > or= 3.0 cm, or a ratio of infrarenal to suprarenal diameter of > or= 1.2, or a history of AAA repair. For the entire CHS cohort, prevalence of aneurysms was 9.5\% (451/4741) overall, with a prevalence among men of 14.2\% (278/1956) and prevalence among women of 6.2\% (173/2785). Variables significantly related to AAA were older age; male sex; history of angina, coronary heart disease, and myocardial infarction; lower ankle-arm blood pressure ratio; higher maximum carotid stenosis; greater intima-media thickness of the internal carotid artery; higher creatinine; lower HDL levels and higher LDL levels; and cigarette smoking. The study has documented the strong association of cardiovascular risk factors and measures of clinical and subclinical atherosclerosis and cardiovascular disease and prevalence of aneurysms. We used a definition that is more sensitive than previously reported (diameter or ratio), which allowed the detection of smaller aneurysms and possibly those at an earlier stage of development. Follow-up of this cohort may lead to new criteria for determining the risk factors for progression of aneurysms.

}, keywords = {Aged, Anthropometry, Aortic Aneurysm, Abdominal, Blood Pressure, Cardiovascular Diseases, Cohort Studies, Comorbidity, Female, Humans, Male, Middle Aged, Pilot Projects, Prevalence, Reproducibility of Results, Risk Factors, Smoking, Ultrasonography, United States}, issn = {1079-5642}, author = {Alcorn, H G and Wolfson, S K and Sutton-Tyrrell, K and Kuller, L H and O{\textquoteright}Leary, D} } @article {1472, title = {Spirometry reference values for healthy elderly blacks. The Cardiovascular Health Study Research Group.}, journal = {Chest}, volume = {110}, year = {1996}, month = {1996 Dec}, pages = {1416-24}, abstract = {

Pulmonary function was assessed by spirometry in 497 black and 2,980 white ambulatory elderly male and female participants of the Cardiovascular Health Study. The quality assurance program prompted technicians to exceed American Thoracic Society recommendations for spirometry. A "healthy" subgroup of 235 black and 1,227 white participants age 65 years and older was identified by excluding current and former smoker, and those with self-reported asthma or emphysema, congestive heart failure, and poor-quality results of spirometry tests, since those factors were associated with a lower FEV1. Reference equations and normal ranges for elderly blacks for measurements of FEV1, FVC, and the FEV1/FVC ratio were then determined from the healthy group. These elderly blacks had an FVC about 6\% lower than elderly whites, even after correcting for standing height, sitting height (trunk length), and age. The popular use of spirometry reference values from studies of middle-aged white subjects by applying a 12\% race correction factor for black patients appears to overestimate predicted values.

}, keywords = {African Continental Ancestry Group, Aged, Aged, 80 and over, European Continental Ancestry Group, Female, Forced Expiratory Volume, Humans, Male, Reference Values, Spirometry, United States, Vital Capacity}, issn = {0012-3692}, author = {Enright, P L and Arnold, A and Manolio, T A and Kuller, L H} } @article {1456, title = {White blood cell counts in persons aged 65 years or more from the Cardiovascular Health Study. Correlations with baseline clinical and demographic characteristics.}, journal = {Am J Epidemiol}, volume = {143}, year = {1996}, month = {1996 Jun 01}, pages = {1107-15}, abstract = {

A higher white blood cell (WBC) count has been shown to be a risk factor for myocardial infarction and stroke in middle-aged populations. This study evaluated the relation between baseline WBC count and other risk factors, as well as subclinical and prevalent disease, in the Cardiovascular Health Study, an epidemiologic study of coronary heart disease and stroke in 5,201 persons aged 65 years or older. Baseline data were collected over a 12-month period in 1989-1990. WBC counts were statistically significantly higher in people with prevalent and subclinical atherosclerotic cardiovascular disease than in those who were free of disease. WBC counts correlated (p < 0.01) positively with coagulation factors, measures of glucose metabolism, creatinine, smoking, and triglycerides. In contrast, WBC counts correlated negatively with high density lipoprotein cholesterol, forced expiratory volume, forced vital capacity, and height. The correlations between WBC counts and risk factors were similar in both the entire cohort and the subgroup of persons who had never smoked. The authors conclude that WBC counts in the elderly are associated with prevalent and subclinical atherosclerotic cardiovascular disease, as well as its risk factors.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Cerebrovascular Disorders, Female, Humans, Leukocyte Count, Leukocytosis, Longitudinal Studies, Male, Myocardial Infarction, Prevalence, Reference Values, Risk Factors, United States}, issn = {0002-9262}, author = {Bovill, E G and Bild, D E and Heiss, G and Kuller, L H and Lee, M H and Rock, R and Wahl, P W} } @article {1488, title = {Incidence of and risk factors for atrial fibrillation in older adults.}, journal = {Circulation}, volume = {96}, year = {1997}, month = {1997 Oct 07}, pages = {2455-61}, abstract = {

BACKGROUND: This study aimed to describe the incidence of atrial fibrillation (AF) among older adults during 3 years of follow-up.

METHODS AND RESULTS: In this cohort study, 5201 adults > or = 65 years old were examined annually on four occasions between June 1989 and May 1993. At baseline, participants answered questionnaires and underwent a detailed examination that included carotid ultrasound, pulmonary function tests, ECG, and echocardiography. Subjects with a pacemaker or AF at baseline (n=357) were excluded. New cases of AF were identified from three sources: (1) annual self-reports, (2) annual ECGs, and (3) hospital discharge diagnoses. Cox proportional-hazards models were used to assess baseline risk factors as predictors of incident AF. Among 4844 participants, 304 developed a first episode of AF during an average follow-up of 3.28 years, for an incidence of 19.2 per 1000 person-years. The onset was strongly associated with age, male sex, and the presence of clinical cardiovascular disease. For men 65 to 74 and 75 to 84 years old, the incidences were 17.6 and 42.7, respectively, and for women, 10.1 and 21.6 events per 1000 person-years. In stepwise models, the use of diuretics, a history of valvular heart disease, coronary disease, advancing age, higher levels of systolic blood pressure, height, glucose, and left atrial size were all associated with an increased risk of AF. The use of beta-blockers and high levels of alcohol use, cholesterol, and forced expiratory volume in 1 second were associated with a reduced risk of AF.

CONCLUSIONS: The incidence of AF in older adults may be higher than estimated by previous population studies. Left atrial size appears to be an important risk factor, and the control of blood pressure and glucose may be important in preventing the development of AF.

}, keywords = {Adult, Aged, Atrial Fibrillation, Blood Glucose, Blood Pressure, Cerebrovascular Disorders, Cohort Studies, Coronary Disease, Electrocardiography, Female, Follow-Up Studies, Hospital Records, Humans, Incidence, Male, Prospective Studies, Risk Factors, United States}, issn = {0009-7322}, author = {Psaty, B M and Manolio, T A and Kuller, L H and Kronmal, R A and Cushman, M and Fried, L P and White, R and Furberg, C D and Rautaharju, P M} } @article {1490, title = {Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {17}, year = {1997}, month = {1997 Oct}, pages = {2167-76}, abstract = {

Blood levels of C-reactive protein (CRP), a marker of inflammation, are related to cardiovascular disease risk. To determine cross-sectional correlates in the elderly, we measured CRP in 400 men and women older than 65 years and free of clinical cardiovascular disease at baseline as part of the Cardiovascular Health Study. Only 2\% of the values were greater than 10 mg/L, the cut-point usually used to identify inflammation. CRP levels appeared tightly regulated, since there were strong bivariate correlations between CRP and the following: inflammation-sensitive proteins such as fibrinogen (r = .52); measures of fibrinolysis such as plasmin-antiplasmin complex (r = .23); pack-years of smoking (r = .30); and body mass index (r = .24; all P values < or = .001). The association with pack-years was independent of the length of time since cessation of smoking. CRP levels were also associated with coagulation factors VIIc, IXc, and Xc; HDL cholesterol (negative) and triglyceride; diabetes status; diuretic use; ECG abnormalities; and level of exercise. Because of effect modification, two multiple linear regression prediction models were developed for CRP, one each for never smokers and ever smokers. An a priori physiologic model was used to guide these analyses, which disallowed the use of other inflammation-sensitive variables such as fibrinogen. In never smokers, the independent predictors were body mass index (+), diabetes status (+), plasmin-antiplasmin complex (+), and the presence of ECG abnormalities (+); this model predicted 15\% of the CRP population variance. In ever smokers, the predictors were body mass index (+), plasmin-antiplasmin complex (+), pack-years of smoking (+), HDL cholesterol (-), and ankle-arm blood pressure index (-); this model predicted 42\% of the population variance. We conclude that levels of CRP in the healthy elderly are tightly regulated and reflect lifetime exposure to smoking as well as level of obesity, ongoing level of fibrinolysis, diabetes status, and level of subclinical atherothrombotic disease. Moreover, exposure to smoking affects the relation of CRP to these other factors.

}, keywords = {Aged, Body Mass Index, C-Reactive Protein, Cardiovascular Diseases, Female, Humans, Male, Multivariate Analysis, Risk Factors, Smoking}, issn = {1079-5642}, author = {Tracy, R P and Psaty, B M and Macy, E and Bovill, E G and Cushman, M and Cornell, E S and Kuller, L H} } @article {1484, title = {Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {17}, year = {1997}, month = {1997 Jun}, pages = {1121-7}, abstract = {

Markers of inflammation, such as C-reactive protein (CRP), are related to risk of cardiovascular disease (CVD) events in those with angina, but little is known about individuals without prevalent clinical CVD. We performed a prospective, nested case-control study in the Cardiovascular Health Study (CHS; 5201 healthy elderly men and women). Case subjects (n = 146 men and women with incident CVD events including angina, myocardial infarction, and death) and control subjects (n = 146) were matched on the basis of sex and the presence or absence of significant subclinical CVD at baseline (average follow-up, 2.4 years). In women but not men, the mean CRP level was higher for case subjects than for control subjects (P < or = .05). In general, CRP was higher in those with subclinical disease. Most of the association of CRP with female case subjects versus control subjects was in the subgroup with subclinical disease; 3.33 versus 1.90 mg/L, P < .05, adjusted for age and time of follow-up. Case-control differences were greatest when the time between baseline and the CVD event was shortest. The strongest associations were with myocardial infarction, and there was an overall odds ratio for incident myocardial infarction for men and women with subclinical disease (upper quartile versus lower three quartiles) of 2.67 (confidence interval [CI] = 1.04 to 6.81), with the relationship being stronger in women (4.50 [CI = 0.97 to 20.8]) than in men (1.75 [CI = 0.51 to 5.98]). We performed a similar study in the Rural Health Promotion Project, in which mean values of CRP were higher for female case subjects than for female control subjects, but no differences were apparent for men. Comparing the upper quintile with the lower four, the odds ratio for CVD case subjects was 2.7 (CI = 1.10 to 6.60). In conclusion, CRP was associated with incident events in the elderly, especially in those with subclinical disease at baseline.

}, keywords = {Aged, Aging, C-Reactive Protein, Cardiovascular Diseases, Case-Control Studies, Female, Humans, Male, Prospective Studies, Sex Factors}, issn = {1079-5642}, author = {Tracy, R P and Lemaitre, R N and Psaty, B M and Ives, D G and Evans, R W and Cushman, M and Meilahn, E N and Kuller, L H} } @article {1570, title = {Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort.}, journal = {Thromb Haemost}, volume = {80}, year = {1998}, month = {1998 Jul}, pages = {134-9}, abstract = {

The majority of fatal acute myocardial infarctions occur in the elderly. Since these events are predominantly thrombotic, we studied the cross-sectional associations of the anticoagulant proteins Antithrombin, Protein C, Protein S. and Tissue Factor Pathway Inhibitor (TFPI) in a subgroup (n = 400) of the Cardiovascular Health Study (a study of healthy men and women > or = 65 years) free of clinical cardiovascular disease (CVD). We did not observe any strong age-associated trends, although Protein C was lower in older women (p < or = 0.001), and TFPI was higher in older men (p < or = 0.01). The inhibitors were highly intercorrelated, and were associated with increased levels of inflammation-sensitive proteins (e.g., fibrinogen. plasminogen), lipids (especially total and LDL-cholesterol), and coagulation factors, such as Factors VIIc, IXc, and Xc. None was associated with the procoagulant markers Prothrombin Fragment F1-2 or Fibrinopeptide A. Only TFPI was associated with subclinical atherosclerosis: ankle-arm index and internal carotid artery stenosis, p trend < or = 0.01; and carotid wall thickness, p trend < or = 0.05. In multivariate analysis the independent predictors of TFPI were levels of fibrinogen; the fibrinolytic marker plasmin-antiplasmin complex; LDL-cholesterol; and carotid wall thickness (R2 for the model = 0.35). In summary, the inhibitors did not appear to increase with age, and were predominantly associated with inflammation markers and lipids. Since markers of thrombin production do increase with age, we hypothesize that an age-related hemostatic imbalance may ensue, with associated increased thrombotic risk. Only TFPI was associated with subclinical CVD, suggesting that it may more closely reflect endothelial damage.

}, keywords = {Aged, Aged, 80 and over, Analysis of Variance, Anticoagulants, Antithrombin III, Biomarkers, Cross-Sectional Studies, Disease Susceptibility, Female, Humans, Lipoproteins, Male, Prevalence, Protein C, Protein S, Reference Values, Risk Factors, Thrombosis}, issn = {0340-6245}, author = {Sakkinen, P A and Cushman, M and Psaty, B M and Kuller, L H and Bajaj, S P and Sabharwal, A K and Boineau, R and Macy, E and Tracy, R P} } @article {1508, title = {Factor V Leiden is not a risk factor for arterial vascular disease in the elderly: results from the Cardiovascular Health Study.}, journal = {Thromb Haemost}, volume = {79}, year = {1998}, month = {1998 May}, pages = {912-5}, abstract = {

Coagulation factor V Leiden is a risk marker for venous thrombosis. For arterial thrombosis no large study to date has included population-based elderly patients. The Cardiovascular Health Study is a longitudinal study of 5,201 men and women over age 65. With 3.4-year follow-up, we studied 373 incident cases of myocardial infarction (MI), angina, stroke. or transient ischemic attack (TIA), and 482 controls. The odds ratios for each event with heterozygous factor V Leiden were: MI, 0.46 (95\% CI 0.17 to 1.25); angina, 1.0 (95\% CI 0.45 to 2.23); stroke, 0.77 (95\% CI 0.35 to 1.70): TIA, 1.33 (95\% CI 0.5 to 3.55); any outcome, 0.83 (95\% CI 0.48 to 1.44). Adjustment for cardiovascular risk factors did not change relationships. In older adults factor V Leiden is not a risk factor for future arterial thrombosis.

}, keywords = {Adult, Age Factors, Aged, Arteries, Factor V, Female, Humans, Male, Middle Aged, Mutation, Risk Factors, Thrombosis}, issn = {0340-6245}, author = {Cushman, M and Rosendaal, F R and Psaty, B M and Cook, E F and Valliere, J and Kuller, L H and Tracy, R P} } @article {1494, title = {Relationship between ApoE, MRI findings, and cognitive function in the Cardiovascular Health Study.}, journal = {Stroke}, volume = {29}, year = {1998}, month = {1998 Feb}, pages = {388-98}, abstract = {

BACKGROUND AND PURPOSE: We determined the relationship between apolipoprotein (Apo)E, MRI, and low cognitive scores.

METHODS: The relationship between age, education, ApoE genotype, MRI examination of the brain, subclinical and clinical cardiovascular disease, and low (<80) score on the Modified Mini-Mental State Examination (3MSE, as modified by Teng and Chui) was evaluated for 3469 black and white participants in the Cardiovascular Health Study (CHS) in years 5 and 6 of the study. The participants were followed for up to 3 years.

RESULTS: The prevalence of scores <80 in years 5 and 6 of the CHS was 8.2\% for participants without and 20.4\% for those with prior history of stroke. Age, race, and education were important determinants of low 3MSE scores. The prevalence of ApoE-4 (odds ratio [OR], 1.6 [1.1 to 2.1]) was directly related to scores <80, as was high ventricular volume (OR, 1.6 [1.2 to 2.3]), high white matter grade (OR, 1.4 [1.1 to 1.9]), and infarctlike lesions (OR, 1.6 [1.2 to 2.1]) on the MRI in the multivariate analysis. A five-point or greater decline in scores over up to 3 years was more often observed for participants with low 3MSE scores at year 5, at older ages, with lower education, and experiencing incident stroke (OR, 3.6 [1.2 to 10.6]), ApoE-4 genotype (OR, 1.8 [1.4 to 2.3]), and with MRI findings of high ventricular volume (OR, 2.0 [1.5 to 2.7]), and infarctlike lesions (OR, 1.2 [0.9 to 1.5]).

CONCLUSIONS: These results demonstrate that vascular changes on MRI, measures of brain atrophy, ApoE-4, and age, education, and race are associated with low cognitive scores among older individuals. The MRI of the brain provides valuable information related to cognitive tests and decline over time. The potential exists for using MRI measurements to identify high-risk individuals for dementia and to test potential interventions to reduce the risk of dementia.

}, keywords = {African Continental Ancestry Group, Aged, Apolipoproteins E, Brain, Cardiovascular Diseases, Cerebral Infarction, Cognition, Cognition Disorders, European Continental Ancestry Group, Female, Genotype, Health Status, Humans, Magnetic Resonance Imaging, Male, Mental Status Schedule, Polymerase Chain Reaction, Risk Factors, Sex Factors, United States}, issn = {0039-2499}, author = {Kuller, L H and Shemanski, L and Manolio, T and Haan, M and Fried, L and Bryan, N and Burke, G L and Tracy, R and Bhadelia, R} } @article {1522, title = {Analytical and biologic variability in measures of hemostasis, fibrinolysis, and inflammation: assessment and implications for epidemiology.}, journal = {Am J Epidemiol}, volume = {149}, year = {1999}, month = {1999 Feb 01}, pages = {261-7}, abstract = {

An increasing number of cardiovascular epidemiologic studies are measuring non-traditional risk markers of disease, most of which do not have established biovariability characteristics. When biovariability data have been reported, they usually represent a short time period, and, in any case, there is little consensus on how the information should be used. The authors performed a long-term (6-month) repeated measures study on 26 healthy individuals, and, using a nested analysis of variance (ANOVA) approach, report on the analytical (CVA), intraindividual (CVI), and between individual (CVG) variability of 12 procoagulant, fibrinolysis, and inflammation assays, including total cholesterol for comparison. The results suggest acceptable analytical variability (CVA < or = 1/2 CVI) for all assays. However, there was a large range of intraindividual variation as a proportion of total variance (2-78\%), and adjusting for intraindividual and between individual variation in bivariate correlations increased the observed correlation by more than 30 percent for three of these assays. Overall, the assays showed a significant increase in intraindividual variation over 6 months (p < 0.05). While these findings suggest that most of these assays have biovariability characteristics similar to cholesterol, there is variation among assays. Some assays may be better suited to epidemiologic studies, and knowledge of an assay{\textquoteright}s biovariability data may be useful in interpreting simple statistics, and in designing multivariate models.

}, keywords = {Adult, Aged, Analysis of Variance, Cardiovascular Diseases, Cholesterol, Epidemiology, Female, Fibrinolysis, Hemostasis, Humans, Inflammation, Male, Middle Aged, Models, Statistical, Multivariate Analysis, Risk Factors}, issn = {0002-9262}, author = {Sakkinen, P A and Macy, E M and Callas, P W and Cornell, E S and Hayes, T E and Kuller, L H and Tracy, R P} } @article {600, title = {Cardiovascular disease in older adults with glucose disorders: comparison of American Diabetes Association criteria for diabetes mellitus with WHO criteria.}, journal = {Lancet}, volume = {354}, year = {1999}, month = {1999 Aug 21}, pages = {622-5}, abstract = {

BACKGROUND: The new fasting American Diabetes Association (ADA) criteria for the diagnosis of diabetes mellitus rely mainly on fasting blood glucose concentrations and use a lower cut-off value for diagnosis than the WHO criteria. We aimed to assess the sensitivity of these criteria for the detection of cardiovascular disease, the main complication of diabetes mellitus in the elderly.

METHODS: We did a cross-sectional and prospective analysis of 4515 participants of the Cardiovascular Health Study, an 8 year longitudinal study designed to identify factors related to the onset and course of cardiovascular disease in adults aged at least 65 years. We calculated the prevalence and incidence of cardiovascular disease for the ADA and WHO criteria.

FINDINGS: There was a higher prevalence of cardiovascular disease among individuals with impaired glucose or newly diagnosed diabetes by both criteria than among those with normal glucose concentrations. However, because fewer individuals had abnormal glucose states by the fasting ADA criteria (22.3\%) than by the WHO criteria (46.8\%), the number of cases of cardiovascular disease attributable to abnormal glucose states was a third of that attributable by the WHO criteria (53 vs 159 cases per 10,000). For the two sets of criteria, the relative risk for incident cardiovascular disease (mean follow-up 5.9 years) was higher in individuals with impaired glucose and newly diagnosed diabetes than in those with normal glucose. Individuals classified as normal by the fasting ADA criteria had a higher absolute number of incident events (455 of 581 events) than those classified as normal by the WHO criteria (269 of 581 events). Fasting ADA criteria were therefore less sensitive than the WHO criteria for predicting cardiovascular disease among individuals with abnormal glucose (sensitivity, 28\% vs 54\%).

INTERPRETATION: The new fasting ADA criteria seem to be less predictive than the WHO criteria for the burden of cardiovascular disease associated with abnormal glucose in the elderly.

}, keywords = {Age Factors, Aged, Blood Glucose, Cardiovascular Diseases, Cross-Sectional Studies, Diabetes Complications, Diabetes Mellitus, Fasting, Female, Glucose Intolerance, Humans, Longitudinal Studies, Male, Prospective Studies, Risk Factors, Sensitivity and Specificity, Societies, Medical, United States, World Health Organization}, issn = {0140-6736}, doi = {10.1016/s0140-6736(98)12030-5}, author = {Barzilay, J I and Spiekerman, C F and Wahl, P W and Kuller, L H and Cushman, M and Furberg, C D and Dobs, A and Polak, J F and Savage, P J} } @article {584, title = {Fibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {19}, year = {1999}, month = {1999 Mar}, pages = {493-8}, abstract = {

Coagulation factor levels predict arterial thrombosis in epidemiological studies, but studies of older persons are needed. We studied 3 plasma antigenic markers of fibrinolysis, viz, plasminogen activator inhibitor-1 (PAI-1), fibrin fragment D-dimer, and plasmin-antiplasmin complex (PAP) for the prediction of arterial thrombosis in healthy elderly persons over age 65. The study was a nested case-control study in the Cardiovascular Health Study cohort of 5201 men and women >/=65 years of age who were enrolled from 1989 to 1990. Cases were 146 participants without baseline clinical vascular disease who developed myocardial infarction, angina, or coronary death during a follow-up of 2.4 years. Controls remained free of cardiovascular events and were matched 1:1 to cases with respect to sex, duration of follow-up, and baseline subclinical vascular disease status. With increasing quartile of D-dimer and PAP levels but not of PAI-1, there was an independent increased risk of myocardial infarction or coronary death, but not of angina. The relative risk for D-dimer above versus below the median value (>/=120 microg/L) was 2.5 (95\% confidence interval, 1.1 to 5.9) and for PAP above the median (>/=5.25 nmol/L), 3.1 (1.3 to 7.7). Risks were independent of C-reactive protein and fibrinogen concentrations. There were no differences in risk by sex or presence of baseline subclinical disease. D-dimer and PAP, but not PAI-1, predicted future myocardial infarction in men and women over age 65. Relationships were independent of other risk factors, including inflammation markers. Results indicate a major role for these markers in identifying a high risk of arterial disease in this age group.

}, keywords = {Age Factors, Aged, Angina Pectoris, Biomarkers, Female, Fibrin Fibrinogen Degradation Products, Fibrinolysin, Fibrinolysis, Follow-Up Studies, Heart Arrest, Humans, Male, Myocardial Infarction, Plasminogen Activator Inhibitor 1, Risk Factors}, issn = {1079-5642}, doi = {10.1161/01.atv.19.3.493}, author = {Cushman, M and Lemaitre, R N and Kuller, L H and Psaty, B M and Macy, E M and Sharrett, A R and Tracy, R P} } @article {588, title = {Hormone replacement therapy, inflammation, and hemostasis in elderly women.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {19}, year = {1999}, month = {1999 Apr}, pages = {893-9}, abstract = {

Lipid-lowering by postmenopausal hormone therapy (HRT) explains only partly the assumed coronary risk reduction associated with therapy. To explore other possible mechanisms, we studied associations of HRT use with inflammation and hemostasis risk markers in women >/=65 years of age. Subjects were selected from 3393 participants in the fourth year examination of the Cardiovascular Health Study, an observational study of vascular disease risk factors. After excluding women with vascular disease, we compared levels of inflammation and hemostasis variables in the 230 women using unopposed estrogen and 60 using estrogen/progestin, with those of 196 nonusers selected as controls. Compared with nonusers, unopposed estrogen use was associated with 59\% higher mean C-reactive protein (P<0.001), but with modestly lower levels of other inflammation indicators, fibrinogen, and alpha-1 acid glycoprotein (P<0.001). Factor VIIc was 16\% higher among estrogen users (P<0.001), but this was not associated with higher thrombin production (prothrombin fragment 1-2), or increased fibrin breakdown (D-dimer). Concentration of plasminogen activator inhibitor-1 was 50\% lower in both using groups (P<0.001) compared with nonusers, and this was associated with higher plasmin-antiplasmin complex: 8\% higher in estrogen and 18\% higher in estrogen/progestin users (P<0. 05). Relationships between the markers and hormone use were less pronounced in estrogen/progestin users, with no association for C-reactive protein except in women in upper 2 tertiles of body mass index (P for interaction, 0.02). The direction and strength of the associations of HRT use with inflammation markers differed depending on the protein, so it is not clear whether HRT confers coronary risk reduction through an inflammation-sensitive mechanism. Associations with hemostasis markers indicated no association with evidence of procoagulation and a possible association with increased fibrinolytic activity.

}, keywords = {Aged, Biomarkers, Case-Control Studies, Cross-Sectional Studies, Estrogens, Female, Hemostasis, Hormone Replacement Therapy, Humans, Inflammation, Progestins, Random Allocation, United Kingdom, United States}, issn = {1079-5642}, doi = {10.1161/01.atv.19.4.893}, author = {Cushman, M and Meilahn, E N and Psaty, B M and Kuller, L H and Dobs, A S and Tracy, R P} } @article {594, title = {Increased blood glucose and insulin, body size, and incident colorectal cancer.}, journal = {J Natl Cancer Inst}, volume = {91}, year = {1999}, month = {1999 Jul 07}, pages = {1147-54}, abstract = {

BACKGROUND: Abdominal obesity--an elevated level of visceral adipose tissue--has been linked to colorectal cancer. Furthermore, elevated levels of visceral adipose tissue have been associated with hyperinsulinemia, and insulin is a growth factor in the colon. We assessed whether waist circumference, a surrogate measure of visceral adipose tissue, and metabolic parameters associated with visceral adipose tissue were related to colorectal cancer.

METHODS: In the Cardiovascular Health Study cohort, we examined the relationship of baseline measurements of body size, glucose, insulin, and lipoproteins to incident colorectal cancer. All P values are two-sided.

RESULTS: Among 5849 participants, 102 incident cases of colorectal cancer were identified. Individuals in the highest quartile of fasting glucose had a nearly twofold increased risk of colorectal cancer (relative risk [RR] = 1.8; 95\% confidence interval [CI] = 1.0-3.1), and the linear trend RR (LT RR = 1.2; 95\% CI = 1.0-1.5) for fasting glucose level was statistically significant (P =. 02). Glucose and insulin levels 2 hours after oral glucose challenge also exhibited statistically significant associations with colorectal cancer (2-hour glucose levels: RR = 2.4 [95\% CI = 1.2-4. 7]/LT RR = 1.3 [95\% CI = 1.0-1.6; P =.02]; 2-hour insulin levels: RR = 2.0 [95\% CI = 1.0-3.8]/LT RR = 1.2 [95\% CI = 1.0-1.5; P =.04]). Analysis of fasting insulin levels suggested a threshold effect, with values above the median associated with colorectal cancer (RR = 1.6; 95\% CI = 1.1-2.4; P =.02). Higher levels of waist circumference were also statistically significantly associated with colorectal cancer (RR = 1.9; 95\% CI = 1.1-3.3; P =.02).

CONCLUSIONS: These data provide, to our knowledge, the first direct evidence of an association between elevated visceral adipose tissue level, its associated metabolic effects, and colorectal cancer.

}, keywords = {Adipose Tissue, Aged, Blood Glucose, Body Constitution, Cholesterol, HDL, Colorectal Neoplasms, Female, Humans, Incidence, Insulin, Male, Prospective Studies, Risk, Triglycerides, Viscera}, issn = {0027-8874}, doi = {10.1093/jnci/91.13.1147}, author = {Schoen, R E and Tangen, C M and Kuller, L H and Burke, G L and Cushman, M and Tracy, R P and Dobs, A and Savage, P J} } @article {585, title = {Relationship of plasmin generation to cardiovascular disease risk factors in elderly men and women.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {19}, year = {1999}, month = {1999 Mar}, pages = {499-504}, abstract = {

Plasmin-alpha2-antiplasmin complex (PAP) marks plasmin generation and fibrinolytic balance. We recently observed that elevated levels of PAP predict acute myocardial infarction in the elderly, yet little is known about the correlates of PAP. We measured PAP in 800 elderly subjects who were free of clinical cardiovascular disease in 2 cohort studies: the Cardiovascular Health Study and the Honolulu Heart Program. Median PAP levels did not differ between the Cardiovascular Health Study (6.05+/-1.46 nmol/L) and the Honolulu Heart Program (6.11+/-1.44 nmol/L), and correlates of PAP were similar in both cohorts. In CHS, PAP levels increased with age (r=0. 30), procoagulant factors (eg, factor VIIc, r=0.15), thrombin activity (prothrombin fragment F1+2, r=0.29), and inflammation-sensitive proteins (eg, fibrinogen, r=0.44; factor VIIIc, r=0.37). PAP was associated with increased atherosclerosis as measured by the ankle-arm index (AAI) (P for trend, }, keywords = {Aged, Aged, 80 and over, alpha-2-Antiplasmin, Antifibrinolytic Agents, Asian Continental Ancestry Group, Cohort Studies, Coronary Disease, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Fibrinolysin, Fibrinolysis, Humans, Insulin Resistance, Male, Multivariate Analysis, Myocardial Infarction, Plasminogen Activator Inhibitor 1, Risk Factors}, issn = {1079-5642}, doi = {10.1161/01.atv.19.3.499}, author = {Sakkinen, P A and Cushman, M and Psaty, B M and Rodriguez, B and Boineau, R and Kuller, L H and Tracy, R P} } @article {593, title = {Traditional risk factors and subclinical disease measures as predictors of first myocardial infarction in older adults: the Cardiovascular Health Study.}, journal = {Arch Intern Med}, volume = {159}, year = {1999}, month = {1999 Jun 28}, pages = {1339-47}, abstract = {

BACKGROUND: Risk factors for myocardial infarction (MI) have not been well characterized in older adults, and in estimating risk, we sought to assess the individual and joint contributions made by both traditional risk factors and measures of subclinical disease.

METHODS: In the Cardiovascular Health Study, we recruited 5888 adults aged 65 years and older from 4 US centers. At baseline in 1989-1990, participants underwent an extensive examination that included traditional risk factors such as blood pressure and fasting glucose level and measures of subclinical disease as assessed by electrocardiography, carotid ultrasonography, echocardiography, pulmonary function, and ankle-arm index. Participants were followed up with semiannual contacts, and all cardiovascular events were classified by the Morbidity and Mortality Committee. The main analytic technique was the Cox proportional hazards model.

RESULTS: At baseline, 1967 men and 2979 women had no history of an MI. After follow-up for an average of 4.8 years, there were 302 coronary events, which included 263 patients with MI and 39 with definite fatal coronary disease. The incidence was higher in men (20.7 per 1000 person-years) than women (7.9 per 1000 person-years). In all subjects, the incidence was strongly associated with age, increasing from 7.8 per 1000 person-years in subjects aged 65 to 69 years to 25.6 per 1000 person-years in subjects aged 85 years and older. Glucose level and systolic blood pressure were associated with the incidence of MI, but smoking and lipid measures were not. After adjustment for age and sex, the significant subclinical disease predictors of MI were borderline or abnormal ejection fraction by echocardiography, high levels of intimal-medial thickness of the internal carotid artery, and a low ankle-arm index. Forced vital capacity and electrocardiographic left ventricular mass did not enter the stepwise model. Excluding subjects with clinical cardiovascular diseases such as prior angina or congestive heart failure at baseline had little effect on these results. Risk factors were generally similar in men and women.

CONCLUSIONS: After follow-up of 4.8 years, systolic blood pressure, fasting glucose level, and selected subclinical disease measures were important predictors of the incidence of MI in older adults. Uncontrolled high blood pressure may explain about one quarter of the coronary events in this population.

}, keywords = {Age Distribution, Aged, Female, Follow-Up Studies, Humans, Incidence, Male, Multivariate Analysis, Myocardial Infarction, Predictive Value of Tests, Proportional Hazards Models, Risk, Risk Factors, Sex Distribution}, issn = {0003-9926}, doi = {10.1001/archinte.159.12.1339}, author = {Psaty, B M and Furberg, C D and Kuller, L H and Bild, D E and Rautaharju, P M and Polak, J F and Bovill, E and Gottdiener, J S} } @article {625, title = {Chlamydia pneumoniae, herpes simplex virus type 1, and cytomegalovirus and incident myocardial infarction and coronary heart disease death in older adults : the Cardiovascular Health Study.}, journal = {Circulation}, volume = {102}, year = {2000}, month = {2000 Nov 07}, pages = {2335-40}, abstract = {

BACKGROUND: Whether serological evidence of prior infection with Chlamydia pneumoniae, herpes simplex virus type 1 (HSV-1), and cytomegalovirus (CMV) is associated with myocardial infarction (MI) and coronary heart disease (CHD) death remains a source of controversy.

METHODS AND RESULTS: We conducted a nested case-control study among participants in the Cardiovascular Health Study, a cohort study of persons aged >/=65 years. Cases experienced an incident MI and CHD death (n=213). Control subjects were matched to cases by age, sex, clinic, year of enrollment, and month of blood draw (n=405). Serum was analyzed for IgG antibodies to C pneumoniae, HSV-1, and CMV. After adjustment for other risk factors, the risk of MI and CHD death was associated with the presence of IgG antibodies to HSV-1 (odds ratio [OR] 2.0, 95\% CI 1.1 to 3.6) but was not associated with the presence of IgG antibodies to either C pneumoniae (OR 1.1, 95\% CI 0.7 to 1.8) or CMV (OR 1.2, 95\% CI 0.7 to 1.9). Although there was little association with low to moderate C pneumoniae antibody titers (

CONCLUSIONS: Among older adults, the presence of IgG antibodies to HSV-1 was associated with a 2-fold increase in the risk of incident MI and CHD death. For C pneumoniae, only high-titer IgG antibodies were associated with an increased risk of MI and CHD death. The presence of IgG antibodies to CMV was not associated with risk among the elderly.

}, keywords = {Adult, Age Factors, Aged, Antibodies, Bacterial, Antibodies, Viral, Case-Control Studies, Chlamydophila pneumoniae, Coronary Disease, Cytomegalovirus, Female, Herpesvirus 1, Human, HIV Antibodies, Humans, Immunoglobulin G, Male, Myocardial Infarction, Risk Factors}, issn = {1524-4539}, doi = {10.1161/01.cir.102.19.2335}, author = {Siscovick, D S and Schwartz, S M and Corey, L and Grayston, J T and Ashley, R and Wang, S P and Psaty, B M and Tracy, R P and Kuller, L H and Kronmal, R A} } @article {612, title = {Coronary artery calcification in older adults with minimal clinical or subclinical cardiovascular disease.}, journal = {J Am Geriatr Soc}, volume = {48}, year = {2000}, month = {2000 Mar}, pages = {256-63}, abstract = {

BACKGROUND: Coronary artery calcification (CAC) reflects the extent of coronary artery atherosclerosis. The extent of coronary artery calcification is not well described in older adults.

OBJECTIVE: To determine the extent of CAC in older adults participating in a large population study of cardiovascular disease (CVD), especially those characterized as having minimal clinical or subclinical cardiovascular disease.

DESIGN: An observational epidemiologic study.

POPULATION: Participants in the Cardiovascular Health Study Cohort, mean age 78 years, who had electron beam computed tomography (EBT) scan of the heart (n = 133); included were 106 persons with no prior evidence of clinical or subclinical CVD.

MEASUREMENTS: Total CAC score was measured using cardiac EBT. Cardiovascular disease and risk factors, as well as carotid ultrasound, electrocardiogram, echocardiogram, and ankle-arm index, had been measured previously to define subclinical disease. Previous cerebral magnetic resonance imaging was also evaluated.

RESULTS: Overall, the CAC scores were higher in those with clinical cardiovascular disease or evidence of subclinical cardiovascular disease than in those with no evidence of disease. For the 106 participants without evidence of clinical or subclinical disease, the median score was 176, compared with 367 in those with subclinical disease and 923 in those with clinical CVD. Seventeen persons had scores of zero. There was little difference in risk factors across quartiles of CAC in the subgroup of 106 with prior characterization of minimal CVD despite the broad range of CAC scores. There was a higher proportion of those with white matter grade > or = 2 by magnetic resonance imaging among those with higher CAC scores (P = .025). Infarct-like lesions prevalence ranged from 12.5\% in the lowest group to 47.1\% in the highest CAC group (P = .019).

CONCLUSIONS: Older adults with evidence of clinical or subclinical CVD have higher total CAC scores. Though the extent of coronary artery calcification was lower in those with minimal evidence of CVD, the range was broad and not explained by CVD risk factors.

}, keywords = {Aged, Aging, Analysis of Variance, Calcinosis, Cardiovascular Diseases, Chi-Square Distribution, Coronary Artery Disease, Coronary Disease, Female, Humans, Male, Risk Factors, Statistics, Nonparametric, Tomography, X-Ray Computed}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2000.tb02643.x}, author = {Newman, A B and Naydeck, B and Sutton-Tyrrell, K and Edmundowicz, D and Gottdiener, J and Kuller, L H} } @article {611, title = {Diabetes mellitus: subclinical cardiovascular disease and risk of incident cardiovascular disease and all-cause mortality.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {20}, year = {2000}, month = {2000 Mar}, pages = {823-9}, abstract = {

Previously diagnosed diabetes mellitus, newly diagnosed diabetes mellitus, and impaired glucose tolerance are important determinants of the risk of clinical cardiovascular disease (CVD). We have evaluated the relation of patients with subclinical CVD, diabetes, and impaired glucose tolerance and "normal" subjects and the risk of clinical CVD in the Cardiovascular Health Study. Diabetes (1343), impaired glucose tolerance (1433), and normal (2421) were defined by World Health Organization criteria at baseline in 1989 to 1990. The average follow-up was 6.4 years (mean age 73 years). Diabetics had a higher prevalence of clinical and subclinical CVD at baseline. Compared with diabetes in the absence of subclinical disease, the presence of subclinical CVD and diabetes was associated with significant increased adjusted relative risk of death (1.5, CI 0.93 to 2.41), relative risk of incident coronary heart disease (1.99, CI 1.25 to 3.19), and incident myocardial infarction (1.93, CI 0.96 to 3.91). The risk of clinical events was greater for participants with a history of diabetes compared with newly diagnosed diabetics at baseline. Compared with nondiabetic nonhypertensive subjects without subclinical disease, patients with a combination of diabetes, hypertension, and subclinical disease had a 12-fold increased risk of stroke. Fasting blood glucose levels were a weak predictor of incident coronary heart disease as were most other risk factors. Subclinical CVD was the primary determinant of clinical CVD among diabetics in the Cardiovascular Health Study.

}, keywords = {Aged, Arteriosclerosis, Coronary Disease, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Female, Humans, Incidence, Male, Multivariate Analysis, Myocardial Infarction, Prevalence, Proportional Hazards Models, Risk Factors, Sex Distribution, Stroke}, issn = {1079-5642}, doi = {10.1161/01.atv.20.3.823}, author = {Kuller, L H and Velentgas, P and Barzilay, J and Beauchamp, N J and O{\textquoteright}Leary, D H and Savage, P J} } @article {606, title = {Evidence of islet cell autoimmunity in elderly patients with type 2 diabetes.}, journal = {Diabetes}, volume = {49}, year = {2000}, month = {2000 Jan}, pages = {32-8}, abstract = {

In light of an occurring growth of elderly people affected by type 2 diabetes and recent observations indicating that type 2 diabetes may be a disease of the innate immune system, we evaluated whether signs of islet cell autoimmunity are associated with an abnormal glucose control, the presence of insulin requirement, or an activation of the acute-phase response in older individuals with type 2 diabetes. GAD65 and IA-2 autoantibodies along with the acute-phase response markers fibrinogen and C-reactive protein were tested in 196 serum samples from patients with type 2 diabetes and in 94 nondiabetic control subjects over the age of 65 years from the Pittsburgh cohort of the Cardiovascular Health Study. Of the diabetic patients, 12\% (24 of 196) had autoantibodies against GAD65 and/or IA-2, a prevalence significantly higher than that found in nondiabetic individuals (1 of 94, 1.1\%; P = 0.001). Type 2 diabetic patients who were positive for GAD65 and/or IA-2 autoantibodies (Ab+), as compared with those negative for these autoantibodies (Ab-), had an abnormal oral glucose tolerance test (OGTT) (P = 0.03) before and a higher frequency of oral hypoglycemic treatment (P = 0.003) at the time of autoantibody testing. No differences were seen in the percentage of insulin requirement in the two groups. Moreover, a statistically significant increase in fibrinogen (P = 0.005) and C-reactive protein levels (P = 0.025) was found in type 2 diabetic patients with high levels of GAD65 and/or IA-2 autoantibodies as compared with Ab-patients and control subjects. In conclusion, in type 2 diabetic subjects > or =65 years old, the presence of islet cell autoimmunity is associated with an impairment of the acute-phase insulin secretion, as revealed by an OGTT. A pronounced activation of the acute-phase response, found to be associated with islet cell autoimmunity, may in part explain this defect in insulin secretion. These findings not only have direct implications for adequate classification and treatment of diabetes in the elderly, but also for understanding the autoimmune/inflammatory mechanisms involved in the pathogenesis of hyperglycemia.

}, keywords = {Aged, Aged, 80 and over, Aging, Autoantibodies, Autoantigens, Autoimmunity, Blood Glucose, C-Reactive Protein, Diabetes Mellitus, Type 2, Female, Fibrinogen, Glucose Tolerance Test, Glutamate Decarboxylase, Humans, Islets of Langerhans, Male, Membrane Proteins, Protein Tyrosine Phosphatases, Receptor-Like Protein Tyrosine Phosphatases, Class 8}, issn = {0012-1797}, doi = {10.2337/diabetes.49.1.32}, author = {Pietropaolo, M and Barinas-Mitchell, E and Pietropaolo, S L and Kuller, L H and Trucco, M} } @article {647, title = {Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study.}, journal = {Arch Intern Med}, volume = {161}, year = {2001}, month = {2001 May 14}, pages = {1183-92}, abstract = {

BACKGROUND: Recent reports have drawn attention to the importance of pulse pressure as a predictor of cardiovascular events. Pulse pressure is used neither by clinicians nor by guidelines to define treatable levels of blood pressure.

METHODS: In the Cardiovascular Health Study, 5888 adults 65 years and older were recruited from 4 US centers. At baseline in 1989-1990, participants underwent an extensive examination, and all subsequent cardiovascular events were ascertained and classified.

RESULTS: At baseline, 1961 men and 2941 women were at risk for an incident myocardial infarction or stroke. During follow-up that averaged 6.7 years, 572 subjects had a coronary event, 385 had a stroke, and 896 died. After adjustment for potential confounders, systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure were directly associated with the risk of incident myocardial infarction and stroke. Only SBP was associated with total mortality. Importantly, SBP was a better predictor of cardiovascular events than DBP or pulse pressure. In the adjusted model for myocardial infarction, a 1-SD change in SBP, DBP, and pulse pressure was associated with hazard ratios (95\% confidence intervals) of 1.24 (1.15-1.35), 1.13 (1.04-1.22), and 1.21 (1.12-1.31), respectively; and adding pulse pressure or DBP to the model did not improve the fit. For stroke, the hazard ratios (95\% confidence intervals) were 1.34 (1.21-1.47) with SBP, 1.29 (1.17-1.42) with DBP, and 1.21 (1.10-1.34) with pulse pressure. The association between blood pressure level and cardiovascular disease risk was generally linear; specifically, there was no evidence of a J-shaped relationship. In those with treated hypertension, the hazard ratios for the association of SBP with the risks for myocardial infarction and stroke were less pronounced than in those without treated hypertension.

CONCLUSION: In this population-based study of older adults, although all measures of blood pressure were strongly and directly related to the risk of coronary and cerebrovascular events, SBP was the best single predictor of cardiovascular events.

}, keywords = {Aged, Blood Pressure, Female, Humans, Male, Myocardial Infarction, Prognosis, Proportional Hazards Models, Prospective Studies, Risk Factors, Stroke, Survival Rate, United States}, issn = {0003-9926}, doi = {10.1001/archinte.161.9.1183}, author = {Psaty, B M and Furberg, C D and Kuller, L H and Cushman, M and Savage, P J and Levine, D and O{\textquoteright}Leary, D H and Bryan, R N and Anderson, M and Lumley, T} } @article {667, title = {Coronary artery calcification in older adults to age 99: prevalence and risk factors.}, journal = {Circulation}, volume = {104}, year = {2001}, month = {2001 Nov 27}, pages = {2679-84}, abstract = {

BACKGROUND: Coronary artery calcification has been proposed as a noninvasive method to assess cardiovascular disease (CVD) risk. However, the prevalence and risk factors for coronary artery calcification in populations >65 years have not been well studied.

METHODS AND RESULTS: Electron beam tomography was performed to assess coronary artery calcium (CAC) in 614 older adults aged, on average, 80 years (range, 67 to 99 years); 367 (60\%) were women, and 143 (23\%) were black. Calcium scores ranged from 0 to 5459. Median scores were 622 for men and 205 for women. Scores increased by age and were lower in blacks than in whites. Nine percent of subjects (n=57) had no CAC, and 31\% (n=190) had a score lower than 100. A history of CVD was associated with calcium score. Age, male sex, white race, CVD, triglyceride level, pack-years of smoking, and asthma, emphysema, or bronchitis (chronic obstructive pulmonary disease) were independently associated with CAC score in the fourth quartile.

CONCLUSIONS: A wide range of CAC scores was observed, suggesting adaptation with aging. CAC may have potential to predict CVD in older adults, but this remains to be determined.

}, keywords = {Age Distribution, Age Factors, Aged, Aged, 80 and over, Black People, Calcinosis, Calcium, Cohort Studies, Comorbidity, Coronary Angiography, Coronary Artery Disease, Coronary Vessels, Demography, Female, Humans, Logistic Models, Male, Predictive Value of Tests, Prevalence, Risk Factors, Sex Distribution, Sex Factors, Tomography, X-Ray Computed, White People}, issn = {1524-4539}, doi = {10.1161/hc4601.099464}, author = {Newman, A B and Naydeck, B L and Sutton-Tyrrell, K and Feldman, A and Edmundowicz, D and Kuller, L H} } @article {659, title = {Post-menopausal hormone therapy and concentrations of protein C and antithrombin in elderly women.}, journal = {Br J Haematol}, volume = {114}, year = {2001}, month = {2001 Jul}, pages = {162-8}, abstract = {

The effects of post-menopausal hormone therapy (HRT) on blood coagulation in elderly women are not well defined. We studied associations of HRT use with levels of natural anticoagulant proteins in a cross-sectional study of 3393 women > or = 65 years of age participating in the Cardiovascular Health Study. Protein C antigen and antithrombin were measured in all users (n = 230 unopposed oestrogen; 60 oestrogen/progestin) and a comparison group of 196 age- and race-matched non-users. Compared with non-users, oestrogen use was associated with higher protein C (4.80 vs. 4.30 microg/ml, P < 0.01). Results were similar for oestrogen/progestin (P > 0.05). In both user groups, antithrombin was lower than in non-users (109\% for each vs. 115\% in non-users, P < 0.001). Adjustment for factors related to prescription of HRT and to anticoagulant protein levels had little impact on the results. For antithrombin, associations with HRT were larger for thinner Caucasian women and black women. Venous thrombosis from HRT may be mediated partly by alterations in antithrombin, but not protein C concentrations. This study extends previous observations to older women, the group at highest risk of venous thromboembolism. Studies of HRT-induced alterations in anticoagulant function in relation to the occurrence of thrombosis with HRT are required.

}, keywords = {Aged, Antithrombins, Black People, Body Mass Index, Cross-Sectional Studies, Estrogen Replacement Therapy, Female, Humans, Logistic Models, Postmenopause, Progestins, Protein C, Risk Factors, Venous Thrombosis, White People}, issn = {0007-1048}, doi = {10.1046/j.1365-2141.2001.02911.x}, author = {Cushman, M and Psaty, B M and Meilahn, E N and Dobs, A S and Kuller, L H} } @article {652, title = {Prevalence of clinical and isolated subclinical cardiovascular disease in older adults with glucose disorders: the Cardiovascular Health Study.}, journal = {Diabetes Care}, volume = {24}, year = {2001}, month = {2001 Jul}, pages = {1233-9}, abstract = {

OBJECTIVE: Clinical cardiovascular disease (CVD) is highly prevalent among people with diabetes. However, there is little information regarding the prevalence of subclinical CVD and its relation to clinical CVD in diabetes and in the glucose disorders that precede diabetes.

RESEARCH DESIGN AND METHODS: Participants in the Cardiovascular Health Study, aged > or = 65 years (n = 5,888), underwent vascular and metabolic testing. Individuals with known disease in the coronary, cerebral, or peripheral circulations were considered to have clinical disease. Those without any clinical disease in whom CVD was detected by ultrasonography, electrocardiography, or ankle arm index in any of the three vascular beds were considered to have isolated subclinical disease.

RESULTS: Approximately 30\% of the cohort had clinical disease, and approximately 60\% of the remainder had isolated subclinical disease. In those with normal glucose status, isolated subclinical disease made up most of the total CVD. With increasing glucose severity, the proportion of total CVD that was clinical disease increased; 75\% of men and 66\% of women with normal fasting glucose status had either clinical or subclinical CVD. Among those with known diabetes, the prevalence was approximately 88\% (odds ratio [OR] 2.46 for men and 4.22 for women, P < 0.0001). There were intermediate prevalences and ORs for those with impaired fasting glucose status and newly diagnosed diabetes.

CONCLUSIONS: Isolated subclinical CVD is common among older adults. Glucose disorders are associated with an increased prevalence of total CVD and an increased proportion of clinical disease relative to subclinical disease.

}, keywords = {Aged, Angina Pectoris, Cardiovascular Diseases, Cerebrovascular Disorders, Cohort Studies, Diabetes Mellitus, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Electrocardiography, Female, Glucose Intolerance, Heart Diseases, Humans, Male, Peripheral Vascular Diseases, Prevalence, United States}, issn = {0149-5992}, doi = {10.2337/diacare.24.7.1233}, author = {Barzilay, J I and Spiekerman, C F and Kuller, L H and Burke, G L and Bittner, V and Gottdiener, J S and Brancati, F L and Orchard, T J and O{\textquoteright}Leary, D H and Savage, P J} } @article {661, title = {The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study.}, journal = {Diabetes}, volume = {50}, year = {2001}, month = {2001 Oct}, pages = {2384-9}, abstract = {

Several studies suggest that inflammation plays a role in the pathogenesis of some glucose disorders in adults. We tested this hypothesis in a longitudinal cohort study of older individuals who had normal fasting glucose (FG) values at baseline. We compared the baseline levels of six inflammatory markers in participants who had developed glucose disorders at follow-up with those of participants whose FG remained normal at follow-up. Participants were members of the Cardiovascular Health Study, a prospective study of risk factors for cardiovascular disease in adults > or =65 years. All 5,888 participants had baseline testing, including FG and markers of inflammation: white blood cell and platelet counts and albumin, fibrinogen, C-reactive protein (CRP), and factor VIIIc levels. At 3-4 years of follow-up, 4,481 (84.5\%) of those who were alive had FG levels retested. Participants who developed diabetes (n = 45) had higher median levels of CRP at baseline than those who remained normoglycemic. On multivariate analysis, those with elevated CRP levels (75th percentile [2.86 mg/l] vs. 25th percentile [0.82 mg/l]) were 2.03 times (95\% confidence intervals, 1.44-2.86) more likely to have diabetes on follow-up. Adjustment for confounders and other inflammatory markers did not appreciably change this finding. There was no relationship between the development of diabetes and other markers of inflammation. Inflammation, as measured by CRP levels, is associated with the development of diabetes in the elderly. Understanding the role of inflammation in the pathogenesis of glucose disorders in this age-group may lead to better classification and treatment of glucose disorders among them.

}, keywords = {Aged, Biomarkers, Blood Glucose, C-Reactive Protein, Cardiovascular Diseases, Cohort Studies, Diabetes Mellitus, Female, Humans, Hypoglycemia, Inflammation, Longitudinal Studies, Male, Reference Values, Risk Factors}, issn = {0012-1797}, doi = {10.2337/diabetes.50.10.2384}, author = {Barzilay, J I and Abraham, L and Heckbert, S R and Cushman, M and Kuller, L H and Resnick, H E and Tracy, R P} } @article {638, title = {The role of comorbidity in the assessment of intermittent claudication in older adults.}, journal = {J Clin Epidemiol}, volume = {54}, year = {2001}, month = {2001 Mar}, pages = {294-300}, abstract = {

The prevalence of intermittent claudication (IC) in older adults by questionnaire is less than 5\% while the prevalence of peripheral arterial disease (PAD) by non-invasive testing is 2-4-fold higher. Comorbid conditions may result in under-reporting intermittent claudication (IC) as assessed by the Rose Questionnaire. We examined characteristics of those who report leg pain in relationship to other comorbid conditions and disability in 5888 participants of the Cardiovascular Health Study (CHS). Older adults with exertional leg pain, not meeting criteria for IC, had a higher prevalence of PAD on non-invasive testing with the ankle-arm index than those without pain, as well as a higher prevalence of arthritis. The pattern of responses suggested that pain for both conditions was reported together. The Rose Questionnaire for IC is specific for PAD, but a negative questionnaire does not indicate a lack of symptoms, rather the presence of PAD along with other conditions that can cause pain.

}, keywords = {Aged, Angina Pectoris, Arterial Occlusive Diseases, Cerebrovascular Disorders, Cohort Studies, Comorbidity, Diabetes Mellitus, Female, Humans, Intermittent Claudication, Leg, Male, Prevalence, Sensitivity and Specificity, Surveys and Questionnaires}, issn = {0895-4356}, doi = {10.1016/s0895-4356(00)00308-5}, author = {Newman, A B and Naydeck, B L and Sutton-Tyrrell, K and Polak, J F and Kuller, L H} } @article {745, title = {Lack of association of the plasminogen activator inhibitor-1 4G/5G promoter polymorphism with cardiovascular disease in the elderly.}, journal = {J Thromb Haemost}, volume = {1}, year = {2003}, month = {2003 Aug}, pages = {1799-804}, abstract = {

Elevated circulating plasminogen activator inhibitor-1 (PAI-1) may increase risk of cardiovascular disease (CVD). The 4G allele of the 4G/5G PAI-1 promoter polymorphism is associated with higher levels of PAI-1. We examined the association of PAI-1 4G/5G genotype and CVD events in the elderly participants of the Cardiovascular Health Study (CHS). We measured 4G/5G genotype in a nested case-control study within the CHS. Cases included incident angina, myocardial infarction (MI), and stroke. 4G/5G genotype was not found to be associated with markers of fibrinolysis or CVD risk in the selected elderly cohort. There were no differences in genotype frequencies by case-control status (5G/5G frequency 16-22\%; chi2P= 0.07). The 5G allele was not associated with incident CVD events when individuals with at least one 5G allele were compared to 4G/4G homozygotes. The presence of at least one 4G allele was likewise not associated with incident CVD when those with 4G/4G and 4G/5G genotypes were compared to 5G/5G homozygotes. Our results suggest that the PAI-1 4G/5G promoter polymorphism is not associated CVD risk factors or incident CVD events in the elderly.

}, keywords = {African Continental Ancestry Group, Aged, Alleles, Cardiovascular Diseases, Case-Control Studies, Cohort Studies, European Continental Ancestry Group, Female, Genotype, Homozygote, Humans, Male, Myocardial Infarction, Plasminogen Activator Inhibitor 1, Polymorphism, Genetic, Promoter Regions, Genetic, Risk}, issn = {1538-7933}, doi = {10.1046/j.1538-7836.2003.00255.x}, author = {Crainich, P and Jenny, N S and Tang, Z and Arnold, A M and Kuller, L H and Manolio, T and Sharrett, A R and Tracy, R P} } @article {870, title = {Benefits of fatty fish on dementia risk are stronger for those without APOE epsilon4.}, journal = {Neurology}, volume = {65}, year = {2005}, month = {2005 Nov 08}, pages = {1409-14}, abstract = {

OBJECTIVE: To compare associations of lean fish vs fatty fish (tuna or other fish) intake with dementia, Alzheimer disease (AD), and vascular dementia (VaD) and in relation to APOE epsilon4 status in the Cardiovascular Health Cognition Study (CHCS).

METHODS: Fish intake was assessed by food frequency questionnaires. Incident dementia, AD, and VaD were determined through a series of cognitive tests, physician{\textquoteright}s assessment, and committee consensus. We used Cox proportional hazards regression to calculate hazard ratios of dementia, AD, and VaD with lean fried fish, fatty fish, or total fish intake, which were then stratified by the presence of APOE epsilon4.

RESULTS: Although consumption of lean fried fish had no protective effect, consumption of fatty fish more than twice per week was associated with a reduction in risk of dementia by 28\% (95\% CI: 0.51 to 1.02), and AD by 41\% (95\% CI: 0.36 to 0.95) in comparison to those who ate fish less than once per month. Stratification by APOE epsilon4 showed this effect to be selective to those without the epsilon4 allele. Adjustment by education and income attenuated the effect.

CONCLUSION: In the Cardiovascular Health Cognition Study, consumption of fatty fish was associated with a reduced risk of dementia and Alzheimer disease for those without the APOE epsilon4 allele.

}, keywords = {Aged, Alzheimer Disease, Apolipoprotein E4, Apolipoproteins E, Cohort Studies, Dementia, Dietary Fats, Unsaturated, Fatty Acids, Omega-3, Feeding Behavior, Female, Fish Oils, Fish Products, Food, Formulated, Genetic Predisposition to Disease, Humans, Incidence, Male, Risk Factors, Socioeconomic Factors, Surveys and Questionnaires}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000183148.34197.2e}, author = {Huang, T L and Zandi, P P and Tucker, K L and Fitzpatrick, A L and Kuller, L H and Fried, L P and Burke, G L and Carlson, M C} } @article {837, title = {Classification of vascular dementia in the Cardiovascular Health Study Cognition Study.}, journal = {Neurology}, volume = {64}, year = {2005}, month = {2005 May 10}, pages = {1539-47}, abstract = {

OBJECTIVE: To describe the diagnostic classification of subjects with incident vascular dementia (VaD) participating in the Cardiovascular Health Study (CHS) Cognition Study.

METHODS: The CHS classified 480 incident cases between 1994 and 1999 among 3,608 CHS participants who had brain MRI in 1992 through 1994 and in 1997 through 1998. The patients were diagnosed before and after reviewing the brain MRI.

RESULTS: The pre-MRI classification showed that 52 participants had VaD and 76 had both Alzheimer disease (AD) and VaD. The post-MRI classification showed that the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) criteria classified 61 subjects as having VaD, the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l{\textquoteright}Enseignement en Neurosciences (NINDS-AIREN) criteria classified 43 subjects as having probable VaD and 10 as possible VaD, and the State of California Alzheimer{\textquoteright}s Disease Diagnostic and Treatment Center (ADDTC) criteria classified 117 as having probable VaD and 96 as possible. The combination of the ADDTC and National Institute of Neurological and Communication Disorders and Stroke-Alzheimer{\textquoteright}s Disease and Related Disorders Association criteria was used to examine the spectrum of vascular disease in dementia. The dementia was attributable to only vascular factors in 56 cases (probable VaD); VaD coexisted with AD in 61 cases, although the VaD component was the leading cause of dementia (probable VaD with AD); AD was the leading cause of dementia in 61 cases (possible VaD and probable AD); and in 29 cases, it was not clear that either AD or VaD was the primary diagnosis (possible AD and possible VaD).

CONCLUSIONS: None of the clinical criteria for VaD identified the same group of subjects. The diagnosis of vascular dementia is difficult in epidemiologic studies because poststroke dementia can be due to Alzheimer disease (AD) and evidence of vascular disease can be found in the MRI of dementia cases without clinical strokes. Whether the clinical progression is related to AD pathology or vascular disease is difficult to establish.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Brain, Cerebral Arteries, Cohort Studies, Dementia, Vascular, Diagnosis, Differential, Disease Progression, Female, Humans, Magnetic Resonance Imaging, Male, Predictive Value of Tests, Stroke, United States}, issn = {1526-632X}, doi = {10.1212/01.WNL.0000159860.19413.C4}, author = {Lopez, O L and Kuller, L H and Becker, J T and Jagust, W J and DeKosky, S T and Fitzpatrick, A and Breitner, J and Lyketsos, C and Kawas, C and Carlson, M} } @article {838, title = {Determinants of vascular dementia in the Cardiovascular Health Cognition Study.}, journal = {Neurology}, volume = {64}, year = {2005}, month = {2005 May 10}, pages = {1548-52}, abstract = {

OBJECTIVE: The authors evaluated 3,375 participants without dementia at the time of MRI in 1991 to 1994 over 5.7 years for incident dementia and type of dementia.

METHODS: Incidence of and risk factors for vascular dementia (VaD) were measured using both pre-MRI and modified State of California Alzheimer{\textquoteright}s Disease Diagnostic and Treatment Centers (ADDTC) post-MRI review and further classified Alzheimer disease (AD) by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer{\textquoteright}s Disease and Related Disorders Association (NINCDS-ADRDA) criteria.

RESULTS: Approximately 44\% (213) of 480 incident dementia cases were classified as possible or probable VaD by ADDTC. The incidence of VaD increased with age and was greater in blacks than whites. Risk factors for VaD included age, Modified Mini-Mental State Examination, high white matter grade, number of MRI infarcts, ventricular size, and history of stroke.

CONCLUSIONS: Vascular disease in the brain is prevalent among incident dementia cases. There is a substantial overlap between cases classified as Alzheimer disease by Neurological and Communicative Disorders and Stroke and the Alzheimer{\textquoteright}s Disease and Related Disorders Association and vascular dementia (VaD) by modified State of California Alzheimer{\textquoteright}s Disease Diagnostic and Treatment Centers criteria. The substantial contribution of vascular disease would be missed without inclusion of MRI. Treatment of risk factors for VaD could have an important impact on incidence of dementia.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, Atrophy, Brain, Cardiovascular Diseases, Cerebral Arteries, Cerebral Infarction, Cohort Studies, Comorbidity, Continental Population Groups, Dementia, Vascular, Female, Humans, Lateral Ventricles, Magnetic Resonance Imaging, Male, Nerve Fibers, Myelinated, Neuropsychological Tests, Risk Factors, Sex Factors}, issn = {1526-632X}, doi = {10.1212/01.WNL.0000160115.55756.DE}, author = {Kuller, L H and Lopez, O L and Jagust, W J and Becker, J T and DeKosky, S T and Lyketsos, C and Kawas, C and Breitner, J C S and Fitzpatrick, A and Dulberg, C} } @article {851, title = {Neuropsychological characteristics of mild cognitive impairment subgroups.}, journal = {J Neurol Neurosurg Psychiatry}, volume = {77}, year = {2006}, month = {2006 Feb}, pages = {159-65}, abstract = {

OBJECTIVE: To describe the neuropsychological characteristics of mild cognitive impairment (MCI) subgroups identified in the Cardiovascular Health Study (CHS) cognition study.

METHODS: MCI was classified as MCI-amnestic type (MCI-AT): patients with documented memory deficits but otherwise normal cognitive function; and MCI-multiple cognitive deficits type (MCI-MCDT): impairment of at least one cognitive domain (not including memory), or one abnormal test in at least two other domains, but who had not crossed the dementia threshold. The MCI subjects did not have systemic, neurological, or psychiatric disorders likely to affect cognition.

RESULTS: MCI-AT (n = 10) had worse verbal and non-verbal memory performance than MCI-MCDT (n = 28) or normal controls (n = 374). By contrast, MCI-MCDT had worse language, psychomotor speed, fine motor control, and visuoconstructional function than MCI-AT or normal controls. MCI-MCDT subjects had memory deficits, though they were less pronounced than in MCI-AT. Of the MCI-MCDT cases, 22 (78.5\%) had memory deficits, and 6 (21.5\%) did not. MCI-MCDT with memory disorders had more language deficits than MCI-MCDT without memory disorders. By contrast, MCI-MCDT without memory deficits had more fine motor control deficits than MCI-MCDT with memory deficits.

CONCLUSIONS: The most frequent form of MCI was the MCI-MCDT with memory deficits. However, the identification of memory impaired MCI groups did not reflect the true prevalence of MCI in a population, as 16\% of all MCI cases and 21.5\% of the MCI-MCDT cases did not have memory impairment. Study of idiopathic amnestic and non-amnestic forms of MCI is essential for an understanding of the aetiology of MCI.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Amnesia, Cognition Disorders, Female, Humans, Male, Neuropsychological Tests, Psychometrics, Reference Values}, issn = {0022-3050}, doi = {10.1136/jnnp.2004.045567}, author = {Lopez, O L and Becker, J T and Jagust, W J and Fitzpatrick, A and Carlson, M C and DeKosky, S T and Breitner, J and Lyketsos, C G and Jones, B and Kawas, C and Kuller, L H} } @article {880, title = {Soluble intracellular adhesion molecule-1 is associated with cardiovascular disease risk and mortality in older adults.}, journal = {J Thromb Haemost}, volume = {4}, year = {2006}, month = {2006 Jan}, pages = {107-13}, abstract = {

BACKGROUND: Intracellular adhesion molecule-1 (ICAM-1) regulates leukocyte-endothelial attachment, a process crucial to atherosclerosis. Circulating soluble ICAM-1 (sICAM-1) may serve as a marker of cardiovascular disease (CVD) progression.

OBJECTIVES: We examined the association of sICAM-1 with measures of subclinical CVD and risk of incident CVD events and death in older men and women (age > or = 65 years) from the Cardiovascular Health Study.

METHODS: Selected participants were free of clinical CVD at baseline. Non-exclusive incident case groups were angina (n = 534), myocardial infarction (n = 304), stroke (n = 327), and death (n = 842; CVD death = 310). A total 643 subjects were free of events during follow-up.

RESULTS: sICAM-1 was positively associated with C-reactive protein, interleukin-6 and fibrinogen and measures of subclinical CVD in these older men and women. In Cox regression models adjusted for age, gender, and race, increasing levels of sICAM-1 were associated with increased risk of all cause mortality in men and women. Hazard ratios (95\% confidence intervals) for a one standard deviation increase in sICAM-1 (89.7 ng mL(-1)) were 1.3 (1.1-1.4) in men and 1.2 (1.1-1.3) in women. sICAM-1 was associated with increased risk of CVD death in women (1.2; 1.0-1.5), but not men (1.1; 0.9-1.3). There were no associations of sICAM-1 with non-fatal CVD events.

CONCLUSIONS: While sICAM-1 was associated with death in older men and women, there was a more marked association between sICAM-1 and CVD death in women.

}, keywords = {Aged, Aged, 80 and over, Angina Pectoris, Biomarkers, Cardiovascular Diseases, Female, Humans, Incidence, Intercellular Adhesion Molecule-1, Male, Mortality, Myocardial Infarction, Regression Analysis, Risk Factors, Sex Factors, Solubility, Stroke}, issn = {1538-7933}, doi = {10.1111/j.1538-7836.2005.01678.x}, author = {Jenny, N S and Arnold, A M and Kuller, L H and Sharrett, A R and Fried, L P and Psaty, B M and Tracy, R P} } @article {909, title = {Acceleration of cerebral ventricular expansion in the Cardiovascular Health Study.}, journal = {Neurobiol Aging}, volume = {28}, year = {2007}, month = {2007 Sep}, pages = {1316-21}, abstract = {

Interactions between prevalent late-life medical conditions and expansion of the cerebral ventricles are not well understood. Thirty elderly subjects received three magnetic resonance (MR) scans each, in 1997-1999, 2002-2004, and 2003-2005. A linear expansion model of MR-measured lateral ventricle volume was estimated for each subject by fitting a line to a plot of their 1997-1999 and 2002-2004 volumes as a function of time. Acceleration in ventricular expansion was defined as the deviation between the 2003-2005 volumes measured from MR and the 2003-2005 volumes predicted by the linear expansion model. Ventricular acceleration was analyzed in a multivariate model with age, race, history of heart disease, diabetes, and hypertension as fixed effects. Ventricular acceleration was significantly higher in non-whites, diabetics, and those without heart disease (p<0.05). Ventricular acceleration was higher in subjects with a history of hypertension, but the difference was not statistically significant (p=0.08). Acceleration of ventricular expansion in the elderly may be related to demographic and cardiovascular factors.

}, keywords = {Aged, Analysis of Variance, Cardiovascular Diseases, Cerebral Ventricles, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Reference Values, Retrospective Studies, Sex Factors, Time Factors}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2006.06.016}, author = {Carmichael, Owen T and Kuller, L H and Lopez, O L and Thompson, P M and Dutton, R A and Lu, A and Lee, S E and Lee, J Y and Aizenstein, H J and Meltzer, C C and Liu, Y and Toga, A W and Becker, J T} } @article {954, title = {Physical activity and white matter lesion progression: assessment using MRI.}, journal = {Neurology}, volume = {68}, year = {2007}, month = {2007 Apr 10}, pages = {1223-6}, abstract = {

We evaluated the association between physical activity and changes in white matter lesions (WMLs) on MRI in a sample of 179 older adults comprising 59 incident cases of Alzheimer disease, 60 persons with mild cognitive impairment, and 60 persons who remained cognitively stable over a median 5-year follow-up. Physical activity was not significantly associated with a decreased rate of periventricular or deep WML progression.

}, keywords = {Activities of Daily Living, Aged, Alzheimer Disease, Cognition Disorders, Cohort Studies, Demyelinating Diseases, Disease Progression, Female, Humans, Magnetic Resonance Imaging, Male, Motor Activity, United States}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000259063.50219.3e}, author = {Podewils, L J and Guallar, E and Beauchamp, N and Lyketsos, C G and Kuller, L H and Scheltens, P} } @article {1046, title = {Fish consumption and risk of subclinical brain abnormalities on MRI in older adults.}, journal = {Neurology}, volume = {71}, year = {2008}, month = {2008 Aug 05}, pages = {439-46}, abstract = {

OBJECTIVE: To investigate the association between fish consumption and subclinical brain abnormalities.

METHODS: In the population-based Cardiovascular Health Study, 3,660 participants age > or =65 underwent an MRI scan in 1992-1994. Five years later, 2,313 were scanned. Neuroradiologists assessed MRI scans in a standardized and blinded manner. Food frequency questionnaires were used to assess dietary intakes. Participants with known cerebrovascular disease were excluded from the analyses.

RESULTS: After adjustment for multiple risk factors, the risk of having one or more prevalent subclinical infarcts was lower among those consuming tuna/other fish > or =3 times/week, compared to <1/month (relative risk 0.74, 95\% CI = 0.54-1.01, p = 0.06, p trend = 0.03). Tuna/other fish consumption was also associated with trends toward lower incidence of subclinical infarcts. Additionally, tuna/other fish intake was associated with better white matter grade, but not with sulcal and ventricular grades, markers of brain atrophy. No significant associations were found between fried fish consumption and any subclinical brain abnormalities.

CONCLUSIONS: Among older adults, modest consumption of tuna/other fish, but not fried fish, was associated with lower prevalence of subclinical infarcts and white matter abnormalities on MRI examinations. Our results add to prior evidence that suggest that dietary intake of fish with higher eicosapentaenoic acid and docosahexaenoic acid content, and not fried fish intake, may have clinically important health benefits.

}, keywords = {Aged, Animals, Brain, Brain Infarction, Cooking, Cross-Sectional Studies, Diet, Female, Fish Products, Fishes, Humans, Magnetic Resonance Imaging, Male, Prospective Studies, Risk}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000324414.12665.b0}, author = {Virtanen, J K and Siscovick, D S and Longstreth, W T and Kuller, L H and Mozaffarian, D} } @article {1031, title = {Knee height and arm span: a reflection of early life environment and risk of dementia.}, journal = {Neurology}, volume = {70}, year = {2008}, month = {2008 May 06}, pages = {1818-26}, abstract = {

OBJECTIVES: To determine if anthropometric measures, as markers of early life environment, are associated with risk of dementia, Alzheimer disease (AD), and vascular dementia (VaD).

METHODS: A total of 2,798 subjects were followed as part of the Cardiovascular Health Cognition Study for an average of 5.4 years; 480 developed dementia. Knee height was measured 3 years prior to and arm span 4 years after the study{\textquoteright}s baseline. Cox proportional hazard models were used to examine their association with subsequent risk of dementia, AD, and VaD.

RESULTS: Among women, greater knee height and arm span were associated with lower risks of dementia (knee height: HR per 1-inch increase 0.84; 95\% CI 0.74-0.96; arm span: HR per 1-inch increase 0.93; 95\% CI 0.88-0.98) and AD (knee height: HR per 1-inch increase 0.78; 95\% CI 0.65-0.93; arm span: HR per 1-inch increase 0.90; 95\% CI 0.85-0.96). Women in the lowest quartile of arm span had approximately 1.5 times greater risk of dementia (HR 1.45; 95\% CI 1.03-2.05) and AD (HR 1.70; 95\% CI 1.10-2.62) than other women. Among men, only arm span was associated with lower risks of dementia (HR per 1-inch increase 0.94; 95\% CI 0.89-1.00) and AD (HR per 1-inch increase 0.92; 95\% CI 0.84-1.00). For each gender, knee height was not associated with VaD, while arm span was associated with a nonsignificant lower risk of VaD.

CONCLUSIONS: Our findings with knee height and arm span are consistent with previous reports and suggest early life environment may play an important role in the determination of future dementia risk.

}, keywords = {Aged, Aged, 80 and over, Aging, Anthropometry, Arm, Body Height, Brain, Child, Child, Preschool, Dementia, Environment, Female, Follow-Up Studies, Humans, Infant, Infant, Newborn, Knee, Male, Middle Aged, Prospective Studies, Risk Factors, Sex Characteristics, Skeleton}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000311444.20490.98}, author = {Huang, T L and Carlson, M C and Fitzpatrick, A L and Kuller, L H and Fried, L P and Zandi, P P} } @article {1034, title = {No advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies.}, journal = {Neurology}, volume = {70}, year = {2008}, month = {2008 Jun 10}, pages = {2291-8}, abstract = {

INTRODUCTION: Observational studies show reduced incidence of Alzheimer dementia (AD) in users of nonsteroidal anti-inflammatory drugs (NSAIDs). One hypothesis holds that the subset of NSAIDs known as selective A beta(42)-lowering agents (SALAs) is responsible for this apparent reduction in AD risk.

METHODS: We pooled individual-level data from six prospective studies to obtain a sufficient sample to examine AD risk in users of SALA vs non-SALA NSAIDs.

RESULTS: Of 13,499 initially dementia-free participants (70,863 person-years), 820 developed incident AD. Users of NSAIDs (29.6\%) showed reduced risk of AD (adjusted hazard ratio [aHR] 0.77, 95\% CI 0.65-0.91). The point estimates were similar for SALAs (aHR 0.87, CI 0.72-1.04) and non-SALAs (aHR 0.75, CI 0.56-1.01). Because 573 NSAID users (14.5\%) reported taking both a SALA and non-SALA, we examined their use alone and in combination. Resulting aHRs were 0.82 (CI 0.67-0.99) for SALA only, 0.60 (CI 0.40-0.90) for non-SALA only, and 0.87 (CI 0.57-1.33) for both NSAIDs (Wald test for differences, p = 0.32). The 40.7\% of participants who used aspirin also showed reduced risk of AD, even when they used no other NSAIDs (aHR 0.78, CI 0.66-0.92). By contrast, there was no association with use of acetaminophen (aHR 0.93, CI 0.76-1.13).

CONCLUSIONS: In this pooled dataset, nonsteroidal anti-inflammatory drug (NSAID) use reduced the risk of Alzheimer dementia (AD). However, there was no apparent advantage in AD risk reduction for the subset of NSAIDs shown to selectively lower A beta(42), suggesting that all conventional NSAIDs including aspirin have a similar protective effect in humans.

}, keywords = {Acetaminophen, Adolescent, Adult, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Analgesics, Non-Narcotic, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Cohort Studies, Female, Humans, Male, Middle Aged, Neuroprotective Agents, Peptide Fragments, Proportional Hazards Models, Prospective Studies, Risk Factors}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000313933.17796.f6}, author = {Szekely, C A and Green, R C and Breitner, J C S and {\O}stbye, T and Beiser, A S and Corrada, M M and Dodge, H H and Ganguli, M and Kawas, C H and Kuller, L H and Psaty, B M and Resnick, S M and Wolf, P A and Zonderman, A B and Welsh-Bohmer, K A and Zandi, P P} } @article {998, title = {NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type.}, journal = {Neurology}, volume = {70}, year = {2008}, month = {2008 Jan 01}, pages = {17-24}, abstract = {

BACKGROUND: Epidemiologic and laboratory studies suggest that nonsteroidal antiinflammatory drugs (NSAIDs) reduce risk of Alzheimer disease (AD). We therefore investigated the association between use of NSAIDs, aspirin, and the non-NSAID analgesic acetaminophen with incidence of dementia and AD.

METHODS: Participants in the Cardiovascular Health Cognition Study included 3,229 individuals aged 65 or older, free of dementia at baseline, with information on medication use. We used Cox proportional hazards regression to estimate the association of medication use with incident all-cause dementia, AD, and vascular dementia (VaD). Additional analyses considered the NSAID-AD relationship as a function of age, presence of at least one epsilon 4 allele at APOE, race, and individual NSAIDs{\textquoteright} reported ability to reduce production of the amyloid-beta peptide variant A beta(42).

RESULTS: Use of NSAIDs was associated with a lower risk of dementia (adjusted hazard ratio or aHR 0.76, 95\% CI or CI 0.60-0.96) and, in particular, AD (aHR 0.63, CI 0.45-0.88), but not VaD (aHR 0.92, CI 0.65-1.28). No similar trends were observed with acetaminophen (aHR 0.99, CI 0.79-1.24). Closer examination suggested AD risk reduction with NSAIDs only in participants having an APOE epsilon 4 allele (aHR 0.34, CI 0.18-0.65; aHR for others 0.88, CI 0.59-1.32). There was no advantage in AD risk reduction with NSAIDs reported to selectively reduce A beta(42).

CONCLUSIONS: Results were consistent with previous cohort studies showing reduced risk of AD in NSAID users, but this association was found only in those with an APOE epsilon 4 allele, and there was no advantage for A beta(42)-lowering NSAIDs.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Anti-Inflammatory Agents, Non-Steroidal, Apolipoproteins E, Cardiovascular System, Dementia, Female, Humans, Incidence, Male, Proportional Hazards Models, Prospective Studies, Risk Factors}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000284596.95156.48}, author = {Szekely, C A and Breitner, J C S and Fitzpatrick, A L and Rea, T D and Psaty, B M and Kuller, L H and Zandi, P P} } @article {1025, title = {Plasma amyloid levels and the risk of AD in normal subjects in the Cardiovascular Health Study.}, journal = {Neurology}, volume = {70}, year = {2008}, month = {2008 May 06}, pages = {1664-71}, abstract = {

OBJECTIVES: To examine the association between incident Alzheimer disease (AD), and plasma A beta 1-40 and A beta 1-42 levels in normal and mild cognitive impairment (MCI) subjects in a subgroup of participants of the Cardiovascular Health Study Cognition Study.

METHODS: We determined the plasma A beta 1-40 and A beta 1-42 levels of 274 nondemented subjects (232 normals and 42 with MCI) in 1998-1999 and repeated the measurements in 2002-2003. The mean age of the subjects at baseline was 79.3 +/- 3.6 years. We examined the association between A beta levels and incident AD over the ensuing 4.5 years, controlling for age, cystatin C level (marker of glomerular function), apolipoprotein E-4 allele, Modified-Mini-Mental State Examination scores, and MRI-identified infarcts.

RESULTS: In an unadjusted prospective model in normal subjects, both A beta 1-40 and A beta 1-42 levels in 1998-1999 were associated with incident AD (n = 55) in 2002-2003 (longitudinal analysis). In the fully adjusted multivariate model, neither A beta 1-42 nor A beta 1-40 nor their ratio was associated with incident AD. However, adjustment had a very small effect on point estimates for A beta 1-42, from an odds ratio (OR) of 1.61 (p = 0.007) in the unadjusted model to an OR of 1.46 (p = 0.08) in the fully adjusted model. In 2002-2003 (cross-sectional analysis), only the unadjusted models showed that both peptides were associated with AD.

CONCLUSIONS: Plasma A beta levels are affected by age and by systemic and CNS vascular risk factors. After controlling for these conditions, A beta-40 and A beta 1-42 are weak predictors of conversion to Alzheimer disease (AD) in normal subjects and are only weakly associated with AD in cross-sectional analysis. Consequently, plasma levels of A beta do not seem to be useful biomarkers for AD.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Apolipoprotein E4, Biomarkers, Brain, Cerebrovascular Disorders, Comorbidity, Cross-Sectional Studies, Cystatin C, Cystatins, Female, Humans, Incidence, Longitudinal Studies, Magnetic Resonance Imaging, Male, Models, Statistical, Neuropsychological Tests, Peptide Fragments, Predictive Value of Tests, Prospective Studies, Reference Values, Risk Factors}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000306696.82017.66}, author = {Lopez, O L and Kuller, L H and Mehta, P D and Becker, J T and Gach, H M and Sweet, R A and Chang, Y F and Tracy, R and DeKosky, S T} } @article {1047, title = {PROC, PROCR and PROS1 polymorphisms, plasma anticoagulant phenotypes, and risk of cardiovascular disease and mortality in older adults: the Cardiovascular Health Study.}, journal = {J Thromb Haemost}, volume = {6}, year = {2008}, month = {2008 Oct}, pages = {1625-32}, abstract = {

BACKGROUND AND OBJECTIVES: Genes encoding protein C anticoagulant pathways are candidates for atherothrombotic and other aging-related disorders.

METHODS: Using a tagSNP approach, and data from the Cardiovascular Health Study (CHS), we assessed associations of common polymorphisms of PROC, PROS1 and PROCR with: (i) plasma protein C, soluble protein C endothelial receptor (sEPCR) and protein S levels measured in a subsample of 336 participants at study entry; and (ii) risk of incident clinical outcomes [coronary heart disease (CHD), stroke, and mortality] in 4547 participants during follow-up. Secondarily, we explored associations between plasma protein C, protein S and sEPCR levels and other candidate genes involved in thrombosis, inflammation, and aging.

RESULTS: The PROCR Ser219Gly polymorphism (rs867186) was strongly associated with higher sEPCR levels, explaining 75\% of the phenotypic variation. The PROCR Ser219Gly variant was also associated with higher levels of circulating protein C antigen. An IL10 polymorphism was associated with higher free protein S levels. The minor alleles of PROC rs2069901 and PROS1 rs4857343 were weakly associated with lower protein C and free protein S levels, respectively. There was no association between PROCR Ser219Gly and risk of CHD, stroke, or mortality. The minor allele of another common PROCR tagSNP, rs2069948, was associated with lymphoid PROCR mRNA expression and with increased risk of incident stroke and all-cause mortality, and decreased healthy survival during follow-up.

CONCLUSIONS: A common PROCR variant may be associated with decreased healthy survival in older adults. Additional studies are warranted to establish the role of PROCR variants in ischemic and aging-related disorders.

}, keywords = {Aged, Aged, 80 and over, Aging, Antigens, CD, Blood Coagulation Factor Inhibitors, Cardiovascular Diseases, Coronary Disease, Endothelial Protein C Receptor, Female, Humans, Inflammation, Male, Middle Aged, Mortality, Polymorphism, Genetic, Protein C, Protein S, Receptors, Cell Surface, Risk, Stroke, Thrombosis}, issn = {1538-7836}, doi = {10.1111/j.1538-7836.2008.03118.x}, author = {Reiner, A P and Carty, C L and Jenny, N S and Nievergelt, C and Cushman, M and Stearns-Kurosawa, D J and Kurosawa, S and Kuller, L H and Lange, L A} } @article {1140, title = {Age, Alzheimer disease, and brain structure.}, journal = {Neurology}, volume = {73}, year = {2009}, month = {2009 Dec 01}, pages = {1899-905}, abstract = {

BACKGROUND: Lack of clear understanding remains on the overlapping atrophy patterns of aging and early Alzheimer disease (AD) pathology in gray matter (GM) of the brain in vivo.

OBJECTIVE: To evaluate the independent and overlapping patterns of GM atrophy in normal aging and AD.

METHODS: A total of 169 cognitively normal subjects and 33 persons with probable AD enrolled in the longitudinal Cardiovascular Health Study-Cognition Study underwent 3-dimensional volumetric MRI scans. Controls remained cognitively normal for at least 5 years after their MRI scans and the probable AD subjects were relatively early in their clinical course with an average modified Mini-Mental State Examination score of 76/100. The scans were analyzed using voxel-based morphometry adjusting for total intracranial volume, gender, education, and race.

RESULTS: With older age, GM volume was lower in the sensorimotor and heteromodal association areas in frontal, temporal, occipital, and parietal lobes, as well as in the cerebellum (false discovery rate p = 0.05). Additional atrophy was observed in the posterior hippocampus, thalamus, and middle cingulate gyrus. By contrast, atrophy was seen in subjects with AD in the anterior hippocampal/parahippocampal regions and the precuneus. Normal aging and AD overlapped in the hippocampal body and the entorhinal cortex.

CONCLUSION: Brain atrophy with aging was observed in supratentorial and infratentorial areas, as well in primary motor, sensory, and heteromodal association regions. Age and Alzheimer disease exert independent gray matter atrophy patterns but these effects overlapped substantially in the hippocampus and entorhinal cortex.

}, keywords = {Aged, Aged, 80 and over, Aging, Alzheimer Disease, Brain, Brain Mapping, Cognition Disorders, Female, Humans, Image Processing, Computer-Assisted, Linear Models, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Retrospective Studies}, issn = {1526-632X}, doi = {10.1212/WNL.0b013e3181c3f293}, author = {Raji, C A and Lopez, O L and Kuller, L H and Carmichael, O T and Becker, J T} } @article {1101, title = {Predicting risk of dementia in older adults: The late-life dementia risk index.}, journal = {Neurology}, volume = {73}, year = {2009}, month = {2009 Jul 21}, pages = {173-9}, abstract = {

OBJECTIVE: To develop a late-life dementia risk index that can accurately stratify older adults into those with a low, moderate, or high risk of developing dementia within 6 years.

METHODS: Subjects were 3,375 participants in the Cardiovascular Health Cognition Study without evidence of dementia at baseline. We used logistic regression to identify those factors most predictive of developing incident dementia within 6 years and developed a point system based on the logistic regression coefficients.

RESULTS: Subjects had a mean age of 76 years at baseline; 59\% were women and 15\% were African American. Fourteen percent (n = 480) developed dementia within 6 years. The final late-life dementia risk index included older age (1-2 points), poor cognitive test performance (2-4 points), body mass index <18.5 (2 points), > or =1 apolipoprotein E epsilon4 alleles (1 point), cerebral MRI findings of white matter disease (1 point) or ventricular enlargement (1 point), internal carotid artery thickening on ultrasound (1 point), history of bypass surgery (1 point), slow physical performance (1 point), and lack of alcohol consumption (1 point) (c statistic, 0.81; 95\% confidence interval, 0.79-0.83). Four percent of subjects with low scores developed dementia over 6 years compared with 23\% of subjects with moderate scores and 56\% of subjects with high scores.

CONCLUSIONS: The late-life dementia risk index accurately stratified older adults into those with low, moderate, and high risk of developing dementia. This tool could be used in clinical or research settings to target prevention and intervention strategies toward high-risk individuals.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Alcohol Drinking, Apolipoprotein E4, Body Mass Index, Carotid Stenosis, Cerebrum, Cognition Disorders, Cohort Studies, Coronary Artery Bypass, Dementia, Female, Genetic Markers, Health Status Indicators, Humans, Logistic Models, Male, Predictive Value of Tests, Risk Assessment, Risk Factors, Risk Reduction Behavior}, issn = {1526-632X}, doi = {10.1212/WNL.0b013e3181a81636}, author = {Barnes, D E and Covinsky, K E and Whitmer, R A and Kuller, L H and Lopez, O L and Yaffe, K} } @article {1239, title = {Physical activity predicts gray matter volume in late adulthood: the Cardiovascular Health Study.}, journal = {Neurology}, volume = {75}, year = {2010}, month = {2010 Oct 19}, pages = {1415-22}, abstract = {

OBJECTIVES: Physical activity (PA) has been hypothesized to spare gray matter volume in late adulthood, but longitudinal data testing an association has been lacking. Here we tested whether PA would be associated with greater gray matter volume after a 9-year follow-up, a threshold could be identified for the amount of walking necessary to spare gray matter volume, and greater gray matter volume associated with PA would be associated with a reduced risk for cognitive impairment 13 years after the PA evaluation.

METHODS: In 299 adults (mean age 78 years) from the Cardiovascular Health Cognition Study, we examined the association between gray matter volume, PA, and cognitive impairment. Physical activity was quantified as the number of blocks walked over 1 week. High-resolution brain scans were acquired 9 years after the PA assessment on cognitively normal adults. White matter hyperintensities, ventricular grade, and other health variables at baseline were used as covariates. Clinical adjudication for cognitive impairment occurred 13 years after baseline.

RESULTS: Walking amounts ranged from 0 to 300 blocks (mean 56.3; SD 69.7). Greater PA predicted greater volumes of frontal, occipital, entorhinal, and hippocampal regions 9 years later. Walking 72 blocks was necessary to detect increased gray matter volume but walking more than 72 blocks did not spare additional volume. Greater gray matter volume with PA reduced the risk for cognitive impairment 2-fold.

CONCLUSION: Greater amounts of walking are associated with greater gray matter volume, which is in turn associated with a reduced risk of cognitive impairment.

}, keywords = {Aged, Aged, 80 and over, Brain, Brain Mapping, Cardiovascular Diseases, Cognition Disorders, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Mental Status Schedule, Motor Activity, Neuropsychological Tests, Odds Ratio, Predictive Value of Tests, Surveys and Questionnaires}, issn = {1526-632X}, doi = {10.1212/WNL.0b013e3181f88359}, author = {Erickson, K I and Raji, C A and Lopez, O L and Becker, J T and Rosano, C and Newman, A B and Gach, H M and Thompson, P M and Ho, A J and Kuller, L H} } @article {6365, title = {Physical activity, inflammation, and volume of the aging brain.}, journal = {Neuroscience}, volume = {273}, year = {2014}, month = {2014 Jul 25}, pages = {199-209}, abstract = {

Physical activity influences inflammation, and both affect brain structure and Alzheimer{\textquoteright}s disease (AD) risk. We hypothesized that older adults with greater reported physical activity intensity and lower serum levels of the inflammatory marker tumor necrosis factor α (TNFα) would have larger regional brain volumes on subsequent magnetic resonance imaging (MRI) scans. In 43 cognitively intact older adults (79.3{\textpm}4.8 years) and 39 patients with AD (81.9{\textpm}5.1 years at the time of MRI) participating in the Cardiovascular Health Study, we examined year-1 reported physical activity intensity, year-5 blood serum TNFα measures, and year-9 volumetric brain MRI scans. We examined how prior physical activity intensity and TNFα related to subsequent total and regional brain volumes. Physical activity intensity was measured using the modified Minnesota Leisure Time Physical Activities questionnaire at year 1 of the study, when all subjects included here were cognitively intact. Stability of measures was established for exercise intensity over 9 years and TNFα over 3 years in a subset of subjects who had these measurements at multiple time points. When considered together, more intense physical activity intensity and lower serum TNFα were both associated with greater total brain volume on follow-up MRI scans. TNFα, but not physical activity, was associated with regional volumes of the inferior parietal lobule, a region previously associated with inflammation in AD patients. Physical activity and TNFα may independently influence brain structure in older adults.

}, keywords = {Aged, Aged, 80 and over, Aging, Alzheimer Disease, Apolipoproteins E, Brain, Female, Humans, Inflammation, Longitudinal Studies, Magnetic Resonance Imaging, Male, Motor Activity, Neuroimmunomodulation, Neuropsychological Tests, Organ Size, Parietal Lobe, Surveys and Questionnaires, Tumor Necrosis Factor-alpha}, issn = {1873-7544}, doi = {10.1016/j.neuroscience.2014.05.005}, author = {Braskie, M N and Boyle, C P and Rajagopalan, P and Gutman, B A and Toga, A W and Raji, C A and Tracy, R P and Kuller, L H and Becker, J T and Lopez, O L and Thompson, P M} }