Grip Strength, Gait Speed and Plasma Markers of Neurodegeneration in Asymptomatic Middle-aged and Older Adults.

BACKGROUND: Pragmatic biomarkers of preclinical dementia would allow for easy and large-scale screening of risk in populations. Physical function measures like grip strength and gait speed are potential predictive biomarkers but their relationship with plasma markers of Alzheimer's Disease and neurodegeneration have not been elucidated. OBJECTIVES: To examine association between physical function measures and plasma markers of Alzheimer's Disease (AD) and neurodegeneration. DESIGN: Cross-sectional and longitudinal analyses. SETTING: Community-based cohort in the city of Framingham, Massachusetts. PARTICIPANTS: 2336 participants of the Framingham Heart Study Offspring cohort with an average age of 61. MEASUREMENTS: Plasma Aß40 and Aß42 were measured in 1998-2001 (Exam-7) and plasma total tau measured 5 years later (Exam-8). Grip strength, fast walk speed and chair stand speed were measured at both exams. Quantification of Aß isoforms in plasma was performed using INNO-BIA assays and plasma total-tau was measured using Quanterix Simoa HD-1 assay. Confounder-adjusted linear regression models examined associations between physical function and plasma markers, Results: Grip strength at Exam-7 was associated with plasma Aß40 (ß -0.006, p-value 0.032) at Exam-7 and plasma total-tau (ß -0.010, p-value 0.001) at Exam-8. Grip strength and fast walk speed at Exam-8 were associated with plasma total-tau at Exam-8 (GS: ß -0.009, p 0.0005; FWS: ß -0.226, p-value <0.0001). Chair stand speed was not associated with plasma markers; Aß42 was not associated with function. CONCLUSION: Grip strength and fast walk speed are associated with plasma markers of neurodegeneration in dementia-free middle aged and older individuals. Both these measures could be used as potential screening tools for identifying individuals at a higher risk for AD and related dementias alongside other validated markers.

Job strain and cognitive decline: a prospective study of the framingham offspring cohort.

BACKGROUND: Workplace stress is known to be related with many behavioral and disease outcomes. However, little is known about its prospective relationship with measures of cognitive decline. OBJECTIVE: To investigate the association of job strain, psychological demands and job control on cognitive decline. METHODS: Participants from Framingham Offspring cohort (n=1429), were assessed on job strain, and received neuropsychological assessment approximately 15 years and 21 years afterwards. RESULTS: High job strain and low control were associated with decline in verbal learning and memory. Job strain was associated with decline in word recognition skills. Active job and passive job predicted decline in verbal learning and memory relative to low strain jobs in the younger subgroup. Active job and demands were positively associated with abstract reasoning skills. CONCLUSIONS: Job strain and job control may influence decline in cognitive performance.

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

Red blood cell ω-3 fatty acid levels and markers of accelerated brain aging.

OBJECTIVE: Higher dietary intake and circulating levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been related to a reduced risk for dementia, but the pathways underlying this association remain unclear. We examined the cross-sectional relation of red blood cell (RBC) fatty acid levels to subclinical imaging and cognitive markers of dementia risk in a middle-aged to elderly community-based cohort. METHODS: We related RBC DHA and EPA levels in dementia-free Framingham Study participants (n = 1575; 854 women, age 67 ± 9 years) to performance on cognitive tests and to volumetric brain MRI, with serial adjustments for age, sex, and education (model A, primary model), additionally for APOE ε4 and plasma homocysteine (model B), and also for physical activity and body mass index (model C), or for traditional vascular risk factors (model D). RESULTS: Participants with RBC DHA levels in the lowest quartile (Q1) when compared to others (Q2-4) had lower total brain and greater white matter hyperintensity volumes (for model A: ß ± SE = -0.49 ± 0.19; p = 0.009, and 0.12 ± 0.06; p = 0.049, respectively) with persistence of the association with total brain volume in multivariable analyses. Participants with lower DHA and ω-3 index (RBC DHA+EPA) levels (Q1 vs. Q2-4) also had lower scores on tests of visual memory (ß ± SE = -0.47 ± 0.18; p = 0.008), executive function (ß ± SE = -0.07 ± 0.03; p = 0.004), and abstract thinking (ß ± SE = -0.52 ± 0.18; p = 0.004) in model A, the results remaining significant in all models. CONCLUSION: Lower RBC DHA levels are associated with smaller brain volumes and a "vascular" pattern of cognitive impairment even in persons free of clinical dementia.

Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline.

OBJECTIVE: Our aim was to test the association of vascular risk factor exposure in midlife with progression of MRI markers of brain aging and measures of cognitive decline. METHODS: A total of 1,352 participants without dementia from the prospective Framingham Offspring Cohort Study were examined. Multivariable linear and logistic regressions were implemented to study the association of midlife vascular risk factor exposure with longitudinal change in white matter hyperintensity volume (WMHV), total brain volume (TBV), temporal horn volume, logical memory delayed recall, visual reproductions delayed-recall (VR-d), and Trail-Making Test B-A (TrB-A) performance a decade later. RESULTS: Hypertension in midlife was associated with accelerated WMHV progression (p < 0.001) and worsening executive function (TrB-A score; p = 0.012). Midlife diabetes and smoking were associated with a more rapid increase in temporal horn volume, a surrogate marker of accelerated hippocampal atrophy (p = 0.017 and p = 0.008, respectively). Midlife smoking also predicted a more marked decrease in total brain volume (p = 0.025) and increased risk of extensive change in WMHV (odds ratio = 1.58 [95%confidence interval 1.07-2.33], p = 0.021). Obesity in midlife was associated with an increased risk of being in the top quartile of change in executive function (1.39 [1.02-1.88], p = 0.035) and increasing waist-to-hip ratio was associated with marked decline in TBV (10.81 [1.44-81.01], p = 0.021). Longitudinal changes in brain structure were significantly correlated with decline in memory and executive function. CONCLUSIONS: Midlife hypertension, diabetes, smoking, and obesity were associated with an increased rate of progression of vascular brain injury, global and hippocampal atrophy, and decline in executive function a decade later.

Depressive symptoms and risk of dementia: the Framingham Heart Study.

OBJECTIVES: Depression may be associated with an increased risk for dementia, although results from population-based samples have been inconsistent. We examined the association between depressive symptoms and incident dementia over a 17-year follow-up period. METHODS: In 949 Framingham original cohort participants (63.6% women, mean age = 79), depressive symptoms were assessed at baseline (1990-1994) using the 60-point Center for Epidemiologic Studies Depression Scale (CES-D). A cutpoint of > or = 16 was used to define depression, which was present in 13.2% of the sample. Cox proportional hazards models adjusting for age, sex, education, homocysteine, and APOE epsilon4 examined the association between baseline depressive symptoms and the risk of dementia and Alzheimer disease (AD). RESULTS: During the 17-year follow-up period, 164 participants developed dementia; 136 of these cases were AD. A total of 21.6% of participants who were depressed at baseline developed dementia compared with 16.6% of those who were not depressed. Depressed participants (CES-D >/=16) had more than a 50% increased risk for dementia (hazard ratio [HR] 1.72, 95% confidence interval [CI] 1.04-2.84, p = 0.035) and AD (HR 1.76, 95% CI 1.03-3.01, p = 0.039). Results were similar when we included subjects taking antidepressant medications as depressed. For each 10-point increase on the CES-D, there was significant increase in the risk of dementia (HR 1.46, 95% CI 1.18-1.79, p < 0.001) and AD (HR 1.39, 95% CI 1.11-1.75, p = 0.005). Results were similar when we excluded persons with possible mild cognitive impairment. CONCLUSIONS: Depression is associated with an increased risk of dementia and AD in older men and women over 17 years of follow-up.

Association of parental dementia with cognitive and brain MRI measures in middle-aged adults.

OBJECTIVES: Studies of autosomal dominant Alzheimer disease (AD) have shown structural and cognitive changes in mutation carriers decades prior to clinical disease. Whether such changes are detectable in offspring of persons with sporadic dementia remains unknown. We related prospectively verified parental dementia to brain MRI and cognitive testing in the offspring, within a 2-generational community-based cohort. METHODS: A total of 717 Framingham offspring (mean age: 59 +/- 8 years) were studied. In multivariate analyses, we compared offspring with and without verified parental dementia (and AD) for 1) performance on tests of memory, abstract reasoning, and cognitive flexibility, and 2) volumetric brain MRI measures of total cerebral brain volume (TCBV), hippocampal volume (HV), and white matter hyperintensity volume (WMHV), assessed cross-sectionally and longitudinally. RESULTS: When testing the association of parental dementia and AD with baseline cognitive performance, we observed an interaction of parental dementia and AD with APOE epsilon4 status (p < 0.002). In APOE epsilon4 carriers only (n = 165), parental dementia was associated with poorer scores on tests of verbal memory (beta = -1.81 +/- 0.53, p < 0.001) and visuospatial memory (beta = -1.73 +/- 0.47, p < 0.001). These associations were stronger for parental AD (beta = -1.97 +/- 0.52, p < 0.001, beta = -1.95 +/- 0.48, p < 0.001), equivalent to 14-16 years of brain aging. Among APOE epsilon4 carriers, offspring of participants with dementia were also more likely to show an annual decline in TCBV in the top quartile (odds ratio = 4.67 [1.26-17.30], p = 0.02). Regardless of APOE epsilon4 status, participants with parental dementia were more likely to be in the highest quartile of decline in executive function test scores (odds ratio = 1.61 [1.02-2.53], p = 0.04). CONCLUSIONS: Among middle-aged carriers of the APOE epsilon4 allele, parental dementia and Alzheimer disease were associated with poorer verbal and visuospatial memory and a higher rate of global brain atrophy.

No advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies.

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.

Inflammatory markers and the risk of Alzheimer disease: the Framingham Study.

OBJECTIVE: To examine whether serum cytokines and spontaneous production of peripheral blood mononuclear cell (PBMC) cytokines are associated with the risk of incident Alzheimer disease (AD). METHODS: We followed 691 cognitively intact community-dwelling participants (mean age 79 years, 62% women) and related PBMC cytokine production (tertiles of spontaneous production of interleukin 1 [IL-1], IL-1 receptor antagonist, and tumor necrosis factor alpha [TNF-alpha]) and serum C-reactive protein and interleukin 6 (IL-6) to the risk of incident AD. RESULTS: Adjusting for clinical covariates, individuals in the top two tertiles (T2 and T3) of PBMC production of IL-1 or the top tertile (T3) of PBMC production of TNF-alpha were at increased risk of developing AD (multivariable-adjusted hazard ratio [HR] for IL-1 T2 = 2.84, 95% CI 1.09 to 7.43; p = 0.03 and T3 = 2.61, 95% CI 0.96 to 7.07; p = 0.06; for TNF-alpha, adjusted HR for T2 = 1.30, 95% CI 0.53 to 3.17; p = 0.57 and T3 = 2.59, 95% CI 1.09 to 6.12; p = 0.031]) compared with those in the lowest tertile (T1). INTERPRETATION: Higher spontaneous production of interleukin 1 or tumor necrosis factor alpha by peripheral blood mononuclear cells may be a marker of future risk of Alzheimer disease (AD) in older individuals. These data strengthen the evidence for a pathophysiologic role of inflammation in the development of clinical AD.

Stroke risk profile, brain volume, and cognitive function: the Framingham Offspring Study.

BACKGROUND: Mid-life stroke risk factors have been related to late-life cognitive impairment. This association may result not only from clinical strokes but also from subclinical brain injury, such as a global atrophy demonstrable on quantitative brain MRI. METHODS: The authors evaluated the community-based cohort of Framingham Offspring Study participants. A total of 1,841 subjects (mean age, 62 years; 857 men, 984 women) who underwent quantitative MRI and cognitive testing between 1999 and 2001 and were free of clinical stroke and dementia constituted our study sample. The authors used age- and sex-adjusted linear regression models to relate previous (1991 to 1995) and recent (1998 to 2001) Framingham Stroke Risk Profile (FSRP) scores to the total cerebral brain volume ratio (TCBVr) on follow-up MRI, and further to relate the TCBVr with education-adjusted scores on neuropsychological tests administered at the time of imaging. RESULTS: There was an inverse association between FSRP scores and TCBVr. The TCBVr also showed a significant positive association with performance on tests of attention (Trails A), executive function (Trails B), and visuospatial function (visual reproduction, Hooper visual organization), but not with performance on tests of verbal memory or naming. CONCLUSIONS: The Framingham Stroke Risk Profile may identify subjects with smaller brains and poorer cognitive function among stroke- and dementia-free subjects, reinforcing the importance of managing stroke risk factors.

Elevated midlife blood pressure increases stroke risk in elderly persons: the Framingham Study.

BACKGROUND: Stroke risk predictions are traditionally based on current blood pressure (BP). The potential impact of a subject's past BP experience (antecedent BP) is unknown. We assessed the incremental impact of antecedent BP on the risk of ischemic stroke. METHODS: A total of 5197 stroke-free subjects (2330 men) in the community-based Framingham Study cohort were enrolled from September 29, 1948, to April 25, 1953, and followed up to December 31, 1998. We determined the 10-year risk of completed initial ischemic stroke for 60-, 70-, and 80-year-old subjects as a function of their current BP (at baseline), recent antecedent BP (average of readings at biennial examinations 1-9 years before baseline), and remote antecedent BP (average at biennial examinations 10-19 years earlier), with adjustment for smoking and diabetes mellitus. Models incorporating antecedent BP were also adjusted for baseline BP. The effect of each BP component (systolic BP, diastolic BP, and pulse pressure) was assessed separately. RESULTS: Four hundred ninety-one ischemic strokes (209 in men) were observed in eligible subjects. The antecedent BP influenced the 10-year stroke risk at the age of 60 years (relative risk per SD increment of recent antecedent systolic BP: women, 1.68 [95% confidence interval, 1.25-2.25]; and men, 1.92 [95% confidence interval, 1.39-2.66]) and at the age of 70 years (relative risk per SD increment of recent antecedent systolic BP: women, 1.66 [95% confidence interval, 1.28-2.14]; and men, 1.30 [95% confidence interval, 0.97-1.75]). This effect was evident for recent and remote antecedent BP, consistent in hypertensive and nonhypertensive subjects, and demonstrable for all BP components. CONCLUSIONS: Antecedent BP contributes to the future risk of ischemic stroke. Optimal prevention of late-life stroke will likely require control of midlife BP.

Multicenter, double-blind, placebo-controlled, multiple-challenge evaluation of reported reactions to monosodium glutamate.

BACKGROUND: The frequency of reactions reported to occur after the consumption of monosodium glutamate (MSG) is the subject of controversy. OBJECTIVE: We conducted a multicenter, multiphase, double-blind, placebo-controlled study with a crossover design to evaluate reactions reportedly caused by MSG. METHODS: In 3 of 4 protocols (A, B, and C), MSG was administered without food. A positive response was scored if the subject reported 2 or more symptoms from a list of 10 symptoms reported to occur after ingestion of MSG-containing foods within 2 hours. In protocol A 130 self-selected reportedly MSG-reactive volunteers were challenged with 5 g of MSG and with placebo on separate days (days 1 and 2). Of the 86 subjects who reacted to MSG, placebo, or both in protocol A, 69 completed protocol B to determine whether the response was consistent and dose dependent. To further examine the consistency and reproducibility of reactions to MSG, 12 of the 19 subjects who responded to 5 g of MSG but not to placebo in both protocols A and B were given, in protocol C, 2 challenges, each consisting of 5 g of MSG versus placebo. RESULTS: Of 130 subjects in protocol A, 50 (38. 5%) responded to MSG only, 17 (13.1%) responded to placebo only (P <. 05), and 19 (14.6%) responded to both. Challenge with increasing doses of MSG in protocol B was associated with increased response rates. Only half (n = 19) of 37 subjects who reacted to 5 g of MSG but not placebo in protocol A reacted similarly in protocol B, suggesting inconsistency in the response. Two of the 19 subjects responded in both challenges to MSG but not placebo in protocol C; however, their symptoms were not reproducible in protocols A through C. These 2 subjects were challenged in protocol D 3 times with placebo and 3 times with 5 g of MSG in the presence of food. Both responded to only one of the MSG challenges in protocol D. CONCLUSION: The results suggest that large doses of MSG given without food may elicit more symptoms than a placebo in individuals who believe that they react adversely to MSG. However, neither persistent nor serious effects from MSG ingestion are observed, and the responses were not consistent on retesting.

The impact of managed care insurance on use of lower-mortality hospitals by children undergoing cardiac surgery in California.

CONTEXT: Managed care plans aggressively seek to contain costs, but few data are available regarding their impact on access to high quality care for their members. OBJECTIVE: To assess the impact of managed care health insurance on use of lower-mortality hospitals for children undergoing heart surgery in California. DESIGN: Retrospective cohort study using state-mandated hospital discharge datasets. SETTING: Pediatric cardiovascular surgical centers in California. PATIENTS: Five thousand seventy-one children admitted for open cardiac surgical procedures during 1992-1994. RESULTS: Hospitals were divided into lower- and higher-mortality groups according to adjusted surgical mortality. Using multivariate logistic regression analysis to control for medical, socioeconomic, demographic, and distance factors, children with managed care insurance were less likely to be admitted to a lower-mortality hospital for surgery relative to children with indemnity insurance (odds ratio:.53; 95% confidence interval:.45,.63). Similar findings resulted when the analysis was stratified by race/ethnicity. In addition, length of stay, a correlate of health care costs, was no longer for children admitted to lower-mortality centers than for those at higher-mortality centers (adjusted difference:.54 days shorter at lower-mortality centers; 95% confidence interval: -1.50,. 41). CONCLUSIONS: During this study, children with managed care insurance had significantly reduced use of lower-mortality hospitals for pediatric heart surgery in California compared with children with indemnity insurance. Further study is necessary to determine the mechanisms of this apparent insurance-specific inequity.

The preclinical phase of alzheimer disease: A 22-year prospective study of the Framingham Cohort.

OBJECTIVES: To relate performance on tests of cognitive ability to the subsequent development of probable Alzheimer disease (pAD) and to identify the pattern of earliest changes in cognitive functioning associated with a diagnosis of pAD. DESIGN: From May 1975 to November 1979, a screening neuropsychological battery was administered to Framingham Study participants. They were followed up prospectively for 22 years and examined at least every 2 years for the development of pAD. SETTING: A community-based center for epidemiological research. PARTICIPANTS: Subjects were 1076 participants of the Framingham Study aged 65 to 94 years who were free of dementia and stroke at baseline (initial) neuropsychological testing. MAIN OUTCOME MEASURE: Presence or absence of pAD during a 22-year surveillance period was related to test performance at initial neuropsychological testing. RESULTS: Lower scores for measures of new learning, recall, retention, and abstract reasoning obtained during a dementia-free period were associated with the development of pAD. Lower scores for measures of abstract reasoning and retention predicted pAD after a dementia-free period of 10 years. CONCLUSIONS: The "preclinical phase" of detectable lowering of cognitive functioning precedes the appearance of pAD by many years. Measures of retention of information and abstract reasoning are among the strongest predictors of pAD when the interval between initial assessment and the development of pAD is long. Arch Neurol. 2000.

Computing estimates of incidence, including lifetime risk: Alzheimer's disease in the Framingham Study. The Practical Incidence Estimators (PIE) macro.

The incidence of disease is estimated in medical and public health applications using various different techniques presented in the statistical and epidemiologic literature. Many of these methods have not yet made their way to popular statistical software packages and their application requires custom programming. We present a macro written in the SAS macro language that produces several estimates of disease incidence for use in the analysis of prospective cohort data. The development of the Practical Incidence Estimators (PIE) Macro was motivated by research in Alzheimer's Disease (AD) in the Framingham Study in which the development of AD has been prospectively assessed over an observation period of 24 years. The PIE Macro produces crude and age-specific incidence rates, overall and stratified by the levels of a grouping variable. In addition, it produces age-adjusted rates using direct standardization to the combined group. The user specifies the width of the age groups and the number of levels of the grouping variable. The PIE macro produces estimates of future risk for user-defined time periods and the remaining lifetime risk conditional on survival event-free to user-specified ages. This allows the user to investigate the impact of increasing age on the estimate of remaining lifetime risk of disease. In each case, the macro provides estimates based on traditional unadjusted cumulative incidence, and on cumulative incidence adjusted for the competing risk of death. These estimates and their respective standard errors, are provided in table form and in an output data set for graphing. The macro is designed for use with survival age as the time variable, and with age at entry into the study as the left-truncation variable; however, calendar time can be substituted for the survival time variable and the left-truncation variable can simply be set to zero. We illustrate the use of the PIE macro using Alzheimer's Disease incidence data collected in the Framingham Study.

Review of alleged reaction to monosodium glutamate and outcome of a multicenter double-blind placebo-controlled study.

Monosodium glutamate (MSG) has a long history of use in foods as a flavor enhancer. In the United States, the Food and Drug Administration has classified MSG as generally recognized as safe (GRAS). Nevertheless, there is an ongoing debate exists concerning whether MSG causes any of the alleged reactions. A complex of symptoms after ingestion of a Chinese meal was first described in 1968. MSG was suggested to trigger these symptoms, which were referred to collectively as Chinese Restaurant Syndrome. Numerous reports, most of them anecdotal, were published after the original observation. Since then, clinical studies have been performed by many groups, with varying degrees of rigor in experimental design ranging from uncontrolled open challenges to double-blind, placebo controlled (DBPC) studies. Challenges in subjects who reported adverse reactions to MSG have included relatively few subjects and have failed to show significant reactions to MSG. Results of surveys and of clinical challenges with MSG in the general population reveal no evidence of untoward effects. We recently conducted a multicenter DBPC challenge study in 130 subjects (the largest to date) to analyze the response of subjects who report symptoms from ingesting MSG. The results suggest that large doses of MSG given without food may elicit more symptoms than a placebo in individuals who believe that they react adversely to MSG. However, the frequency of the responses was low and the responses reported were inconsistent and were not reproducible. The responses were not observed when MSG was given with food.

Low cholesterol as a risk factor for primary intracerebral hemorrhage: A case-control study.

We performed a case-control study to assess the relationship between primary intracerebral hemorrhage (ICH) and low serum cholesterol. Prospectively recruited, fully evaluated patients with ICH were compared to two independent control groups, one based in a primary care practice and one population-based. Low cholesterol was defined by the sex-specific lowest quintile of the primary care controls. The proportion of ICH cases with low cholesterol >3 months posthemorrhage was significantly greater than in controls (42 vs. 20% in either control group, p < 0.01). Subgroup analysis showed an overrepresentation of low cholesterols in probable hypertensive hemorrhage (47%, p < 0.05) but not in probable cerebral amyloid angiopathy (27%, p = 0.5). Low cholesterol increased the odds for hemorrhage 2.25-fold (1.12-4.50) after adjustment for age and apolipoprotein E genotype. These data confirm an increased risk for primary ICH associated with low cholesterol, a relationship that may apply specifically to hemorrhages from hypertensive vasculopathy.

Influence of the history on physicians' interpretations of girls' genital findings.

OBJECTIVE: Because physicians customarily obtain histories before examining children in cases of possible sexual abuse, and because the resulting diagnostic opinions can influence important social and legal decisions, we investigated whether clinical histories influence physicians' interpretations of girls' genital findings. DESIGN: In mailed questionnaires, 1387 randomly selected Fellows of the American Academy of Pediatrics and all 802 members of four professional groups concerned with child abuse or pediatric gynecology were asked to interpret seven simulated cases. Respondents were asked to interpret seven additional cases in separate questionnaires mailed 4 months later. Both sets of cases involved the same seven photographs of girls' external genitalia. However, in six of the seven case pairs, the histories in the two questionnaires differed in the extent to which they suggested sexual abuse. In the remaining (control) pair, the same history was presented in both questionnaires. RESULTS: Of 2189 physicians, 1114 (50.9%) responded. Responses from 604 physicians (54.2%) were eligible for analysis. Overall, the genital findings were interpreted most consistently by the most experienced physicians and least consistently by the least experienced physicians. The proportion of physicians whose interpretations of a photograph reversed in the direction suggested by the change in the associated history from "no indication of abuse" to "probable abuse," or vice versa, ranged for experienced physicians from none to 5.6%; for moderately experienced physicians from 1.6% to 19.8%; and for inexperienced physicians from 3.6% to 27.2%. This difference between the experience groups was statistically significant in four case pairs. Mean interpretation scores for genital findings changed significantly when the histories changed in two case pairs for the experienced physicians, in five pairs for the moderately experienced physicians, and in all six pairs for the inexperienced physicians. CONCLUSIONS: In some cases and especially for less experienced physicians, diagnostic expectation appears likely to influence physicians' interpretations of girls' genital findings. Physicians should be alert to the possibility of diagnostic expectation bias and its potentially serious social and legal consequences.

Lifetime risk of developing coronary heart disease.

BACKGROUND: The lifetime risk of developing coronary heart disease has not been estimated in a general population. We investigated the lifetime risks of initial coronary events at different ages. METHODS: We assessed data for 7733 participants in the Framingham Heart Study, who had been examined at least once at age 40-94 years between 1971 and 1975, found to be free of coronary heart disease, and then followed up. We estimated the lifetime risks of coronary heart disease (angina pectoris, coronary insufficiency, myocardial infarction, or death from coronary heart disease) by multiple-decrement life-table methods. FINDINGS: The 7733 patients were followed up for a total of 109,948 person-years. Overall, 1157 participants developed coronary heart disease. 1312 died from non-coronary heart disease causes. Lifetime risk of coronary heart disease at age 40 years was 48.6% (95% CI 45.8-51.3) for men and 31.7% (29.2-34.2) for women. At age 70 years, lifetime risk was 34.9% (31.2-38.7) for men and 24.2% (21.4-27.0) for women. After we excluded isolated angina pectoris as an initial event, the lifetime risk of coronary artery disease events at age 40 years was 42.4% for men and 24.9% for women. INTERPRETATION: Lifetime risk at age 40 years is one in two for men and one in three for women. Even at age 70 years it is one in three for men and one in four for women. This knowledge may promote efforts in education, screening, and treatment for prevention of coronary heart disease in younger and older patients.