The effect of stimulus type and background noise on hearing abilities of the round goby Neogobius melanostomus.

The auditory abilities of the round goby Neogobius melanostomus were quantified using auditory evoked potential recordings, using tone bursts and conspecific call stimuli. Fish were tested over a range of sizes to assess effects of growth on hearing ability. Tests were also run with and without background noise to assess the potential effects of masking in a natural setting. Neogobius melanostomus detected tone bursts from 100 to 600 Hz with no clear best frequency in the pressure domain but were most sensitive to 100 Hz tone stimuli when examined in terms of particle acceleration. Responses to a portion of the N. melanostomus call occurred at a significantly lower threshold than responses to pure tone stimulation. There was no effect of size on N. melanostomus hearing ability, perhaps due to growth of the otolith keeping pace with growth of the auditory epithelium. Neogobius melanostomus were masked by both ambient noise and white noise, but not until sound pressure levels were relatively high, having a 5-10 dB threshold shift at noise levels of 150 dB re 1 µPa and higher but not at lower noise levels.

Fas ligand/Fas-mediated apoptosis in human coronary artery smooth muscle cells: therapeutic implications of fratricidal mode of action.

OBJECTIVE: This study aimed to determine the mode of action of Fas ligand (FasL)/Fas at mediating apoptosis so as to evaluate the potential of FasL in gene therapy for restenosis. METHODS: Passaged human coronary artery smooth muscle (HCASM) cells were infected with recombinant adenoviral vectors expressing murine FasL. Various parameters of FasL expression and apoptosis were measured using FACS, immunofluorescence, calorimetric, and cytotoxicity assays. RESULTS: Most HCASM cells under normal growth conditions expressed Fas and were shown to be susceptible to membrane bound but not soluble FasL. However, some FasL expressing cells survived for up to 7 days. These surviving cells were observed to be spatially distributed and were not in direct physical contact with each other. Upon examination, it was determined that although the majority of the surviving cells expressed FasL, only 30% expressed both Fas and FasL. These cells were capable of inducing apoptosis of target cells and some were also susceptible to FasL expressing cells, provided that the effector and target cells were in close physical contact. FasL/Fas-mediated apoptosis was inhibited by p35, a baculovirus gene that inhibits caspases. Additionally, in contrast to HCASM cells, neither membrane-bound nor soluble FasL induced apoptosis in coronary artery endothelial cells. CONCLUSIONS: FasL expressing HCASM cells do not undergo FasL/Fas mediated "suicide" but kill neighboring cells bearing Fas in a "fratricidal" manner. A small population of HCASM cells expresses no surface Fas. These results imply that HCASM cells transduced in vivo with FasL may serve as "scavengers" and exert a bystander effect on surrounding cells that may be enhanced by co-expression of p35. As FasL-mediated apoptosis occurs in coronary arterial smooth muscle but not endothelial cells, FasL may also offer an advantage over other genes for use in restenosis since the latter may indiscriminately delay re-endothelialization at the sites of gene.

Enhancement of Fas ligand-induced inhibition of neointimal formation in rabbit femoral and iliac arteries by coexpression of p35.

Adenovirus-mediated gene transfer of Fas ligand (FasL) inhibits neointimal formation in balloon-injured rat carotid arteries. Vascular smooth muscle (VSM) cells coexpressing murine FasL and p35, a baculovirus gene that inhibits caspase activity, are not susceptible to FasL-mediated apoptosis in vitro but are capable of inducing apoptosis of VSM cells that do not express p35. We reasoned that coexpression of p35 in FasL-transduced VSM cells in vivo would promote their survival, enhance FasL-induced apoptosis of adjacent VSM cells, and thereby facilitate a greater inhibition of neointimal formation. In balloon-injured rabbit femoral arteries, either Ad2/FasL/p35 or Ad2/FasL was infused into the injured site and withdrawn 20 min later. Both vectors induced a dose-dependent reduction (p < 0.05) of the neointima-to-media ratio when assessed 14 days later. However, Ad2/FasL/p35 exhibited a significantly greater inhibition of neointimal formation than Ad2/FasL. In a more clinically relevant model of restenosis, rabbit iliac arteries were injured with an angioplasty catheter under fluoroscopic guidance. Adenoviral vectors were delivered locally to the injured site over a period of 2 min, using a porous infusion balloon catheter. Twenty-eight days after gene transfer angiographic and histologic assessments indicated a significant (p < 0.05) inhibition of iliac artery lumen stenosis and neointimal formation by Ad2/FasL/p35 (5 x 10(11) particles per artery). The extent of inhibition was comparable to that achieved with Ad2/TK, an adenoviral vector encoding thymidine kinase (5 x 10(11) particles per artery) and coadministration of ganciclovir for 7 days. These data suggest that coexpression of p35 in FasL-transduced VSM cells is more potent at inhibiting neointimal formation and as such represents an improved gene therapy approach for restenosis.

Implementation of a practical digital imaging system for routine gross photography in an autopsy environment.

BACKGROUND: The autopsy environment places stringent requirements on a digital imaging system. These requirements must be addressed if the system is to be functional, easy to use, and reliable. DESIGN: After clearly defining the requirements for such a system, we implemented routine digital imaging in a busy academic autopsy suite. RESULTS: The new technology was immediately accepted by both the resident staff and the technical staff. Although a 35-mm camera was always available for traditional photography, it was rarely used. An interesting side effect of implementing digital imaging was a nearly twofold increase in the number of images taken per autopsy case. The requirements, features, and utility of a digital imaging system are discussed. CONCLUSION: Digital imaging in an autopsy environment can be both practical and cost-effective. It provides many advantages over traditional 35-mm photography and can be the first step toward numerous additional improved services.

Profile for estimating risk of heart failure.

CONTEXT: We devised a risk appraisal function to assess the hazard of heart failure in persons who are predisposed by coronary disease, hypertension, or valvular heart disease. OBJECTIVE: To provide general practitioners and internists with a cost-effective method to select people at high risk who are likely to have impaired left ventricular systolic function and may therefore require further evaluation and aggressive preventive measures. METHODS: The routinely measured risk factors used in constructing the heart failure profile include age, electrocardiographic left ventricular hypertrophy, cardiomegaly on chest x-ray film, heart rate, systolic blood pressure, vital capacity, diabetes mellitus, evidence of myocardial infarction, and valvular disease or hypertension. Based on 486 heart failure cases during 38 years of follow-up, 4-year probabilities of failure were computed using the pooled logistic regression model for each sex; a simple point score system was employed. A multivariate profile was also produced without the vital capacity or chest x-ray film because these may not be readily available in some clinical settings. RESULTS: Using the risk factors that make up the multivariate risk formulation-derived from ordinary office procedures-the probability of developing heart failure can be estimated and compared with the average risk for persons of the same age and sex. Using this risk profile, 60% of events in men and 73% in women occurred in subjects in the top quintile of multivariate risk. CONCLUSIONS: Using this multivariate risk formulation, it is possible to identify high-risk candidates for heart failure who are likely to have a substantial yield of positive findings when tested for objective evidence of presymptomatic left ventricular dysfunction. The risk profile may also identify candidates who are at high risk for heart failure because of multiple, marginal risk factor abnormalities that might otherwise be overlooked.

Long-term influence of fibrinogen on initial and recurrent cardiovascular events in men and women.

Examination of the long-term relation of a single fibrinogen determination to initial and recurrent atherosclerotic cardiovascular events over 20 years of follow-up revealed a powerful and comparably independent impact on initial events in both sexes but an influence on recurrent events only in men.

Selective changes in laminin adhesion and alpha 6 beta 4 integrin regulation are associated with the initial steps in keratinocyte maturation.

In skin, the distribution of integrins is compartmentalized. Whereas the alpha 6 beta 4 integrin complex is polarized to the basal portion of proliferating cells in the basal layer juxtaposed to the basement membrane, alpha 3 beta 1 integrin receptors are localized on the cell surface surrounding basal and suprabasal cells, suggesting beta 1 integrins mediate both cell-matrix and cell-cell interactions. As initiation of maturation in skin is associated with the detachment of cells from the basement membrane, the early loss of alpha 6 beta 4, but not alpha 3 beta 1, integrin expression could be a determining factor in the transition from the proliferating to a differentiating keratinocyte. We have studied the regulation of adhesion potential and integrin expression during differentiation of mouse basal keratinocytes culture in 0.05 mM Ca2+ medium and induced to differentiate in 0.12 mM Ca2+ medium. Within 12-24 h after elevation of Ca2+, a selective loss of the alpha 6 beta 4 integrin complex is associated with the induction of the spinous cell marker keratin 1. This early differentiation phenotype coincides with loss of cell attachment mediated by alpha 6 beta 4 to laminins 1 and 5 but not a fibronectin or collagen IV. Selective loss of attachment to laminin is also detected in spinous cells isolated from newborn epidermis in vivo. The loss of alpha 6 and beta 4 protein expression is a consequence of transcriptional and posttranscriptional events, including reduction in mRNA transcripts, reduced synthesis of the alpha 6 protein, and enhanced processing of the alpha 6 and beta 4 chains as determined by Western blots and pulse-chase experiments in metabolically labeled keratinocytes. Selective processing of the beta 4 intracellular domain is detected before loss of beta 4 from the cell surface in basal keratinocytes, and this process is accelerated during differentiation. Whereas early keratinocyte maturation is linked to the selective loss of the alpha 6 beta 4 complex, loss of both beta 1 and beta 4 integrin mRNA and protein occurs as cells proceed to later stages in the differentiation program as induced by 0.5 mM Ca2+ or suspension culture. These conditions are characterized by accelerated expression of transglutaminase; reduced keratin 1 protein; loss of adhesion to fibronectin, laminin 1, laminin 5, and collagen IV; and rapid cell death. Contributing to the down-regulation of beta 1 integrins during terminal differentiation is a selective sensitivity of alpha 3 beta 1 but not alpha 6 beta 4 to down-regulation by transforming growth factors beta 1 and beta 2, factors that are also expressed differentially in normal skin. This study indicates that down-regulation of the alpha 6 beta 4 but not beta 1 integrins occurs during the initial steps of keratinocyte differentiation and is associated with detachment from the laminin matrix. Such changes could contribute an important signal to initiate the process of terminal keratinocyte differentiation.

Relationship between plasma homocysteine, vitamin status and extracranial carotid-artery stenosis in the Framingham Study population.

Recent studies demonstrated associations between occlusive vascular disease and hyperhomocysteinemia of both genetic and nutritional origin. In the present study we analyzed plasma samples from the 20th biannual examination of the Framingham Heart Study cohort to determine distribution of plasma homocysteine concentrations with emphasis on relationships to B vitamins and prevalence of carotid artery stenosis. Results showed that homocysteine exhibited strong inverse association with plasma folate and weaker associations with plasma vitamin B-12 and pyridoxal-5'-phosphate (PLP). Homocysteine was also inversely associated with intakes of folate and vitamin B-6, but not vitamin B-12. Prevalence of high homocysteine (>14 micromol/l) was 29.3% in this cohort, and inadequate plasma concentrations of one or more B vitamins appear to contribute to 67% of the cases of high homocysteine. Prevalence of stenosis > or = 25% was 43% in men and 34% in women with an odds ratio of 2.0 for individuals in the highest homocysteine quartile (> or = 14.4 micromol/l) compared with those in the lowest quartile (< or = 9.1 micromol/l), after adjustment for sex, age, high density lipoprotein cholesterol, systolic blood pressure and cigarette smoking (Ptrend < 0.001). Plasma concentrations of folate and pyridoxal-5'-phosphate and folate intake were inversely associated with extracranial carotid stenosis after adjustment for age, sex and other risk factors.

Differential regulation of integrins and extracellular matrix binding in epidermal differentiation and squamous tumor progression.

Cell surface receptors of the integrin family regulate physiological and pathological processes in skin, including proliferation, differentiation, and malignant transformation. In skin, integrins are compartmentalized. While alpha 6 beta 4 is restricted to the basal surface of basal cells, beta 1 integrins are expressed in basal and suprabasal layers. In vivo and in Ca(2+)-induced differentiation of mouse keratinocytes in vitro, the loss of attachment to laminin via alpha 6 beta 4 integrin is an early event associated with initiation of spinous differentiation. The restricted expression of alpha 6 beta 4 to the basal cells in normal skin is disrupted early in the development of squamous cancer, where benign papillomas at high risk for malignant progression express alpha 6 beta 4 suprabasally in an expanded proliferative compartment. The aberrant suprabasal alpha 6 beta 4 is associated with reduced keratin 1 expression and upregulation of keratin 13, keratin 8, and gamma-glutamyltranspeptidase. During malignant conversion, the increase in alpha 6 beta 4 protein and mRNA is associated with novel expression of an alternatively spliced form of the alpha 6 subunit, alpha 6B. The induction of alpha 6B both in vivo and in vitro is particularly high in malignant cells produced by transduction of both v-fos and v-rasHa oncogenes into normal keratinocytes where it was associated with increased attachment to laminin. Furthermore, binding to laminin is increased by introduction of alpha 6B into a papilloma cell line. These results establish a link between squamous tumor progression and the upregulation of the alpha 6 beta 4 integrin and suggest that expression of alpha 6B could be functionally relevant to interaction of tumor cells with the laminin matrix during malignant conversion.

Secular trends in long-term sustained hypertension, long-term treatment, and cardiovascular mortality. The Framingham Heart Study 1950 to 1990.

BACKGROUND: Cardiovascular morbidity and mortality result from the chronic processes involved in hypertension. However, long-term sustained (LTS) hypertension has received little attention. METHODS AND RESULTS: Trends in the prevalence of LTS hypertension and its treatment were assessed in 1950, 1960, and 1970 among three cohorts of men and women in the Framingham Heart Study (Mantel-Haenszel test). Cardiovascular disease (CVD) incidence and mortality were compared between patients with LTS hypertension with and without long-term treatment by use of the chi 2 test. Cox proportional hazards regression analysis was used to estimate 10-year risk of death as a function of risk factor levels and treatment. Prevalence of LTS hypertension rose from 138 to 208 per 1000 between the 1950 and 1970 male cohorts (P < .01), while prevalence fell from 253 to 198 per 1000 between the female cohorts (P < .02). Long-term treatment increased 51% between the male cohorts and 45% between the female cohorts (both P < .001). While CVD incidence was similar (26% versus 25%), all-cause mortality was significantly lower among men with long-term treatment (31% versus 43%; P < .05), and CVD mortality was less than half (13% versus 28%; P < .01). Among treated women, all-cause mortality was 21% (versus 34%; P < .01), and CVD mortality was 9% (versus 19%; P < .01). Ten-year risk of CVD death for patients with LTS hypertension with long-term treatment compared with those without was 0.40 (95% CI, 0.27 to 0.60). CONCLUSIONS: This investigation of LTS hypertension, its treatment, and its sequelae in a free-living general population confirms the reduction in CVD mortality demonstrated in more short-term clinical trials of hypertension therapy in select patient groups.

Concept of bridging the gap from youth to adulthood.

Clinical atherosclerotic cardiovascular disease reaches substantial incidence beginning at age 45 years in men and age 55 years in women but has its onset in childhood. Lesions progress in relation to exposure to identified risk factors and, once initiated, tend to be self-perpetuating. Because predisposing factors are often initiated in childhood, interventions beginning early in life are optimal for prevention of adult disease. Even genetically predisposed people usually require an unfavorable lifestyle for the atherogenic trait to be expressed. No combination of risk factors entirely accounts for the increase in clinical atherosclerotic events with advancing age. This may be a reflection of longer exposure to risk factors or impaired ability to cope with them in advanced age. The declining risk factor risk ratios with advancing age may be a consequence of the selective early removal of those most susceptible from the population at risk. Risk of major cardiovascular events increases about 2.5-fold with each 10 years of age, even in people without major risk factors who are considered at low risk for atherosclerotic cardiovascular events. However, at any age vulnerability to cardiovascular events is strongly influenced by the burden of risk factors. Decreased risk ratios with advanced age are offset by a greater absolute risk. The female advantage over men erodes with age, with the menopause and with acquisition of an unfavorable lipid profile and glucose intolerance.

Baldness and coronary heart disease rates in men from the Framingham Study.

The authors assessed the relation between the extent and progression of baldness and coronary heart disease. Baldness was assessed twice, in 1956 and in 1962, in a cohort of 2,017 men from Framingham, Massachusetts. Extent of baldness was classified in terms of number of bald areas: no areas bald (n = 153), one area bald (n = 420), two areas bald (n = 587), and all areas bald (n = 857). Men who were assessed both times and who had two or fewer bald areas during the first evaluation were classified into one of three groups: "mild or no progression," "moderate progression," or "rapid progression." The cohort was followed for up to 30 years for new occurrences of coronary heart disease, coronary heart disease death, cardiovascular disease, and death due to any cause. The relations between the extent and progression of baldness and the aforementioned outcomes were assessed using a Cox proportional hazards model, adjusting for age and other known cardiovascular disease risk factors. Extent of baldness was not associated with any of the outcomes. However, the amount of progression of baldness was associated with coronary heart disease occurrence (relative risk (RR) = 2.4, 95% confidence interval (CI) 1.3-4.4), coronary heart disease mortality (RR = 3.8, 95% CI 1.9-7.7), and all-cause mortality (RR = 2.4, 95% CI 1.5-3.8). Rapid hair loss may be a marker for coronary heart disease.

Newly diagnosed atrial fibrillation and acute stroke. The Framingham Study.

BACKGROUND AND PURPOSE: When atrial fibrillation (AF) is first documented at the time of onset of acute stroke, it is difficult to establish a temporal relationship between AF and stroke. Did AF precede and precipitate the stroke, or did the arrhythmia appear as a result of stroke? Following the course of the newly diagnosed AF may help to clarify this relationship. METHODS: The Framingham Study cohort of 5070 members, aged 30 to 62 years and free of cardiovascular disease at entry, has been under surveillance for the development of cardiovascular disease, including stroke. We followed the course of AF, which was documented for the first time on or soon after hospital admission for stroke. RESULTS: During 38 years of follow-up, 115 of 656 initial stroke events occurred in association with AF: 89 had previously documented AF, 21 had AF discovered for the first time on admission for the stroke, and 5 were admitted with sinus rhythm but developed AF after admission. Of the 21 subjects with AF diagnosed on admission, in 12 (57%) AF persisted thereafter (chronic AF). Among the other 9 persons presenting with nonpersistant AF, paroxysms recurred in 3 (14%) and became chronic AF in 4 (19%). AF was transient and did not recur in only 2 persons (10%). Of the 5 subjects who developed AF after admission, AF was sustained from the initial diagnosis in 2 and recurred in paroxysms or became established as chronic in 3. CONCLUSIONS: Ninety-two percent (24/26) of subjects presenting with newly discovered AF at the time of acute stroke continued to have this rhythm disturbance in a chronic or paroxysmal form. In only 2 subjects (8%) was the arrhythmia short-lived and nonrecurrent. These follow-up data suggest that in most instances AF was probably the precipitant rather than the consequence of stroke.

Left atrial size and the risk of stroke and death. The Framingham Heart Study.

BACKGROUND: The medical literature contains conflicting reports on the association of left atrial (LA) enlargement with risk of stroke. The relation of LA size to risk of stroke and death in the general population remains largely unexplored. METHODS AND RESULTS: Subjects 50 years of age and older from the Framingham Heart Study were studied to assess the relations between echocardiographic LA size and risk of stroke and death. During 8 years of follow-up, 64 of 1371 (4.7%) men and 73 of 1728 (4.2%) women sustained a stroke, and 296 (21.6%) men and 271 (15.7%) women died. Sex-specific Cox proportional-hazards models were adjusted for age, hypertension, diabetes, atrial fibrillation, smoking, ECG left ventricular (LV) hypertrophy, and congestive heart failure or myocardial infarction. After multivariable adjustment, for every 10-mm increase in LA size, the relative risk of stroke was 2.4 in men (95% CI, 1.6 to 3.7) and 1.4 in women (95% CI, 0.9 to 2.1); the relative risk of death was 1.3 in men (95% CI, 1.0 to 1.5) and 1.4 in women (95% CI, 1.1 to 1.7). Adjusting for ECG LV mass/height attenuated the relation of LA size to stroke and death. CONCLUSIONS: After multivariable adjustment, LA enlargement remained a significant predictor of stroke in men and death in both sexes. The relation of LA enlargement to stroke and death appears to be partially mediated by LV mass.

Development of health risk appraisal functions in the presence of multiple indicators: the Framingham Study nursing home institutionalization model.

A health risk appraisal function is a mathematical model designed to estimate the risk or probability of a person's mortality or morbidity for various diseases based upon risk factors such as age, medical history and smoking behaviour. The Framingham Study has contributed substantially to the development and use of these for endpoints such as mortality and incidence of coronary heart disease and other cardiovascular diseases. This paper discusses a methodology for the development of health risk appraisal functions when the number of potential risk factors is large and illustrates it with sex specific functions for nursing home institutionalization. The methodology involves grouping variables substantively into sets, applying principal component factor analysis and variable clustering to obtain substantively meaningful composite scores, ranking these in order of substantive importance, and then entering these with a hierarchical ordering into a Cox proportional hazard regression.

A splice variant of alpha 6 integrin is associated with malignant conversion in mouse skin tumorigenesis.

The epithelial-specific integrin alpha 6 beta 4 is suprabasally expressed in benign skin tumors (papillomas) and is diffusely expressed in carcinomas associated with an increase in the proliferating compartment. Analysis of RNA samples by reverse transcriptase-PCR and DNA sequencing revealed that chemically or oncogenically induced papillomas (n = 8) expressed a single transcript of the alpha 6 subunit, identified as the alpha 6 A splice variant. In contrast, carcinomas (n = 13) expressed both alpha 6A and an alternatively spliced form, alpha 6B. Primary keratinocytes and a number of keratinocyte cell lines that vary in biological potential from normal skin, to benign papillomas, to well-differentiated slowly growing carcinomas exclusively expressed alpha 6A. However, I7, an oncogene-induced cell line that produces highly invasive carcinomas, expressed both alpha 6A and alpha 6B transcript and protein. The expression of alpha 6B in I7 cells was associated with increased attachment to a laminin matrix compared to cell lines exclusively expressing alpha 6A. Furthermore, introduction of an alpha 6B expression vector into a papilloma cell line expressing alpha 6A increased laminin attachment. When a papilloma cell line was converted to an invasive carcinoma by introduction of the v-fos oncogene, the malignant cells expressed both alpha 6A and alpha 6B, while the parent cell line and cells transduced with v-jun or c-myc, which retained the papilloma phenotype, expressed only alpha 6A. Comparative analysis of alpha 6B expression in cell lines and their derived tumors indicate that alpha 6B transcripts are more abundant in tumors than cell lines, and alpha 6B is expressed to a greater extent in poorly differentiated tumors. These results establish a link between malignant conversion and invasion of squamous tumor cells and the regulation of transcript processing of the alpha 6 beta 4 integrin.

Role of smoking in the U-shaped relation of cholesterol to mortality in men. The Framingham Study.

Elevated mortality has been reported at extremes of the serum total cholesterol distribution, with increased coronary mortality reported at high total cholesterol levels and increased cancer and non-cardiovascular/non-cancer mortality at low total cholesterol levels. The authors used data collected on 1,959 males aged 35-69 years from the fourth Framingham Study examination to analyze the relations between total serum cholesterol levels and 409 coronary deaths, 325 cancer deaths, and 534 other deaths for a 32-year follow-up. Age- and risk factor-adjusted Cox regressions were computed. Nonlinear (U-shaped) relations were investigated with the use of quadratic regression and with dummy variables using the 160-199 mg/dl group as the comparison group. Subset analyses investigated the relation in smokers and men who drank > or = 14 alcoholic drinks per week. All analyses were repeated removing those with existing cardiovascular disease and cancer and those who died during the first 5 years of follow-up. A significant U-shaped relation with all-cause mortality was noted, as were an inverse relation to cancer mortality and a monotonic increasing relation with coronary disease mortality. In subset analyses, the association of low serum cholesterol (< 160 mg/dl) with cancer mortality was observed in men who smoked cigarettes. Compared with the 160-199 mg/dl group, the relative risk was 3.72 (p = 0.0001, 95% confidence interval 1.91-7.25). Studies of the relation of low total serum cholesterol levels, cigarette smoking, and cancer are needed.

The 'preclinical phase' of probable Alzheimer's disease. A 13-year prospective study of the Framingham cohort.

OBJECTIVE: To evaluate the interval between the onset of detectable cognitive impairment and clinical diagnosis in individuals with probable Alzheimer's disease (AD), and to identify the pattern of the earliest changes in cognition in probable AD. DESIGN: Longitudinal follow-up of a community-based cohort sample. In 1976 through 1978, a screening neuropsychological examination was administered to Framingham Study participants. These subjects were then followed up prospectively for development of probable AD for up to 13 years. SETTING: This study was conducted at a community-based center for epidemiologic research. PARTICIPANTS: The surveillance sample consisted of 1045 participants in the Framingham Study aged 65 to 88 years who were free of dementia at the time of the neuropsychological screening examination. MAIN OUTCOME MEASURES: Scores on a group of neuropsychological tests were entered into a series of age- and education-adjusted multiple regression procedures, with the presence or absence of probable AD as the outcome variable. RESULTS: Considered individually, most of the screening neuropsychological measures were significantly related to later AD diagnosis. When stepwise regression procedures were employed, only measures of verbal memory and immediate auditory attention span remained significantly related to AD diagnosis. Of note, subjects later diagnosed with probable AD performed at higher levels than normal subjects on the Digit Span test at initial screening. Regression results were essentially unchanged even when the AD sample was restricted to those individuals for whom the screening examination preceded the clinical onset of dementia by 7 years or more. CONCLUSIONS: These findings support previous contentions that a "preclinical phase" of detectable cognitive deficits can precede the clinical diagnosis of probable AD by many years, and they also support the hypothesis that problems with secondary verbal memory are among the first signs of AD.

Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis.

BACKGROUND: Epidemiologic studies have identified hyperhomocysteinemia as a possible risk factor for atherosclerosis. We determined the risk of carotid-artery atherosclerosis in relation to both plasma homocysteine concentrations and nutritional determinants of hyperhomocysteinemia. METHODS: We performed a cross-sectional study of 1041 elderly subjects (418 men and 623 women; age range, 67 to 96 years) from the Framingham Heart Study. We examined the relation between the maximal degree of stenosis of the extracranial carotid arteries (as assessed by ultrasonography) and plasma homocysteine concentrations, as well as plasma concentrations and intakes of vitamins involved in homocysteine metabolism, including folate, vitamin B12, and vitamin B6. The subjects were classified into two categories according to the findings in the more diseased of the two carotid vessels: stenosis of 0 to 24 percent and stenosis of 25 to 100 percent. RESULTS: The prevalence of carotid stenosis of > or = 25 percent was 43 percent in the men and 34 percent in the women. The odds ratio for stenosis of > or = 25 percent was 2.0 (95 percent confidence interval, 1.4 to 2.9) for subjects with the highest plasma homocysteine concentrations (> or = 14.4 mumol per liter) as compared with those with the lowest concentrations (< or = 9.1 mumol per liter), after adjustment for sex, age, plasma high-density lipoprotein cholesterol concentration, systolic blood pressure, and smoking status (P < 0.001 for trend). Plasma concentrations of folate and pyridoxal-5'-phosphate (the coenzyme form of vitamin B6) and the level of folate intake were inversely associated with carotid-artery stenosis after adjustment for age, sex, and other risk factors. CONCLUSIONS: High plasma homocysteine concentrations and low concentrations of folate and vitamin B6, through their role in homocysteine metabolism, are associated with an increased risk of extracranial carotid-artery stenosis in the elderly.