Plasma Aß42/Aß40 and phospho-tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer's disease.

INTRODUCTION: Incorporating blood-based Alzheimer's disease biomarkers such as tau and amyloid beta (Aß) into screening algorithms may improve screening efficiency. METHODS: Plasma Aß, phosphorylated tau (p-tau)181, and p-tau217 concentration levels from AHEAD 3-45 study participants were measured using mass spectrometry. Tau concentration ratios for each proteoform were calculated to normalize for inter-individual differences. Receiver operating characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by > 20 Centiloids. Mixture of experts analysis assessed the value of including tau concentration ratios into the existing predictive algorithm for amyloid positron emission tomography status. RESULTS: The area under the receiver operating curve (AUC) was 0.87 for Aß42/Aß40, 0.74 for phosphorylated variant p-tau181 ratio (p-tau181/np-tau181), and 0.92 for phosphorylated variant p-tau217 ratio (p-tau217/np-tau217). The Plasma Predicted Centiloid (PPC), a predictive model including p-tau217/np-tau217, Aß42/Aß40, age, and apolipoprotein E improved AUC to 0.95. DISCUSSION: Including plasma p-tau217/np-tau217 along with Aß42/Aß40 in predictive algorithms may streamline screening preclinical individuals into anti-amyloid clinical trials. CLINICALTRIALS: gov Identifier: NCT04468659 HIGHLIGHTS: The addition of plasma phosphorylated variant p-tau217 ratio (p-tau217/np-tau217) significantly improved plasma biomarker algorithms for identifying preclinical amyloid positron emission tomography positivity. Prediction performance at higher NAV Centiloid levels was improved with p-tau217/np-tau217. All models generated for this study are incorporated into the Plasma Predicted Centiloid (PPC) app for public use.

Racial and ethnic differences in plasma biomarker eligibility for a preclinical Alzheimer's disease trial.

INTRODUCTION: In trials of amyloid-lowering drugs for Alzheimer's disease (AD), differential eligibility may contribute to under-inclusion of racial and ethnic underrepresented groups. We examined plasma amyloid beta 42/40 and positron emission tomography (PET) amyloid eligibility for the ongoing AHEAD Study preclinical AD program (NCT04468659). METHODS: Univariate logistic regression models were used to examine group differences in plasma and PET amyloid screening eligibility. RESULTS: Of 4905 participants screened at time of analysis, 1724 were plasma eligible to continue in screening: 13.3% Hispanic Black, 24.7% Hispanic White, 20.8% non-Hispanic (NH) Asian, 24.7% NH Black, and 38.9% NH White. Plasma eligibility differed across groups in models controlling for covariates (odds ratio from 1.9 to 4.0 compared to the NH White reference group, P < 0.001). Among plasma eligible participants, PET eligibility did not differ by group. DISCUSSION: These results suggest that prevalence of brain amyloid pathology differed, but that eligibility based on plasma was equally effective across racial and ethnic group members. HIGHLIGHTS: Plasma amyloid eligibility is lower in underrepresented racial and ethnic groups. In plasma eligible adults, positron emission tomography eligibility rates are similar across race and ethnicity. Plasma biomarker tests may be similarly effective across racial and ethnic groups.

Clinical validation of the PrecivityAD2 blood test: A mass spectrometry-based test with algorithm combining %p-tau217 and Aß42/40 ratio to identify presence of brain amyloid.

BACKGROUND: With the availability of disease-modifying therapies for Alzheimer's disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment. METHODS: High-throughput, mass spectrometry-based assays were used to measure %p-tau217 and amyloid beta (Aß)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET. RESULTS: The area under the receiver operating characteristic curve (AUC-ROC) for %p-tau217 (0.94) was statistically significantly higher than that for p-tau217 concentration (0.91). The AUC-ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status. DISCUSSION: The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET.

Regulatory review of novel therapeutics--comparison of three regulatory agencies.

BACKGROUND: The upcoming reauthorization of the Prescription Drug User Fee Act focuses on improving the review process for new drug applications at the Food and Drug Administration (FDA). METHODS: Using publicly available information from the FDA, the European Medicines Agency (EMA), and Health Canada, we compared the time for completion of the first review and the total review time for all applications involving novel therapeutic agents approved by the three regulatory agencies from 2001 through 2010 and determined the geographic area in which each novel therapeutic agent was first approved for use. RESULTS: There were 510 applications for novel therapeutic agents approved from 2001 through 2010--225 by the FDA, 186 by the EMA, and 99 by Health Canada; among the applications, there were 289 unique agents. The median length of time for completion of the first review was 303 days (interquartile range, 185 to 372) for applications approved by the FDA, 366 days (interquartile range, 310 to 445) for those approved by the EMA, and 352 days (interquartile range, 255 to 420) for those approved by Health Canada (P<0.001 for the comparison across the three agencies). The median total review time was also shorter at the FDA than at the EMA or Health Canada (P=0.002). Among the 289 unique novel therapeutic agents, 190 were approved in both the United States and Europe (either by the EMA or through the mutual recognition process), of which 121 (63.7%) were first approved in the United States; similarly, 154 were approved in both the United States and Canada, of which 132 (85.7%) were first approved in the United States. CONCLUSIONS: For novel therapeutic agents approved between 2001 and 2010, the FDA reviewed applications involving novel therapeutics more quickly, on average, than did the EMA or Health Canada, and the vast majority of these new therapeutic agents were first approved for use in the United States. (Funded by the Pew Charitable Trusts.).

Use of a Blood Biomarker Test Improves Economic Utility in the Evaluation of Older Patients Presenting with Cognitive Impairment.

More than 16 million Americans living with cognitive impairment warrant a diagnostic evaluation to determine the cause of this disorder. The recent availability of disease-modifying therapies for Alzheimer's disease (AD) is expected to significantly drive demand for such diagnostic testing. Accurate, accessible, and affordable methods are needed. Blood biomarkers (BBMs) offer advantages over usual care amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers in these regards. This study used a budget impact model to assess the economic utility of the PrecivityAD® blood test, a clinically validated BBM test for the evaluation of brain amyloid, a pathological hallmark of AD. The model compared 2 scenarios: (1) baseline testing involving usual care practice, and (2) early use of a BBM test before usual care CSF and PET biomarker use. At a modest 40% adoption rate, the BBM test scenario had comparable sensitivity and specificity to the usual care scenario and showed net savings in the diagnostic work-up of $3.57 million or $0.30 per member per month in a 1 million member population, translating to over $1B when extrapolated to the US population as a whole and representing a 11.4% cost reduction. Savings were driven by reductions in the frequency and need for CSF and PET testing. Additionally, BBM testing was associated with a cost savings of $643 per AD case identified. Use of the PrecivityAD blood test in the clinical care pathway may prevent unnecessary testing, provide cost savings, and reduce the burden on both patients and health plans.

Acceptable performance of blood biomarker tests of amyloid pathology - recommendations from the Global CEO Initiative on Alzheimer's Disease.

Anti-amyloid treatments for early symptomatic Alzheimer disease have recently become clinically available in some countries, which has greatly increased the need for biomarker confirmation of amyloid pathology. Blood biomarker (BBM) tests for amyloid pathology are more acceptable, accessible and scalable than amyloid PET or cerebrospinal fluid (CSF) tests, but have highly variable levels of performance. The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to consider the minimum acceptable performance of BBM tests for clinical use. Amyloid PET status was identified as the reference standard. For use as a triaging test before subsequent confirmatory tests such as amyloid PET or CSF tests, the BBM Workgroup recommends that a BBM test has a sensitivity of ≥90% with a specificity of ≥85% in primary care and ≥75-85% in secondary care depending on the availability of follow-up testing. For use as a confirmatory test without follow-up tests, a BBM test should have performance equivalent to that of CSF tests - a sensitivity and specificity of ~90%. Importantly, the predictive values of all biomarker tests vary according to the pre-test probability of amyloid pathology and must be interpreted in the complete clinical context. Use of BBM tests that meet these performance standards could enable more people to receive an accurate and timely Alzheimer disease diagnosis and potentially benefit from new treatments.

A blood biomarker test for brain amyloid impacts the clinical evaluation of cognitive impairment.

OBJECTIVE: The objective of this study was to examine clinicians' patient selection and result interpretation of a clinically validated mass spectrometry test measuring amyloid beta and ApoE blood biomarkers combined with patient age (PrecivityAD® blood test) in symptomatic patients evaluated for Alzheimer's disease (AD) or other causes of cognitive decline. METHODS: The Quality Improvement and Clinical Utility PrecivityAD Clinician Survey (QUIP I, ClinicalTrials.gov Identifier: NCT05477056) was a prospective, single-arm cohort study among 366 patients evaluated by neurologists and other cognitive specialists. Participants underwent blood biomarker testing and received an amyloid probability score (APS), indicating the likelihood of a positive result on an amyloid positron emission tomography (PET) scan. The primary study outcomes were appropriateness of patient selection as well as result interpretation associated with PrecivityAD blood testing. RESULTS: A 95% (347/366) concordance rate was noted between clinicians' patient selection and the test's intended use criteria. In the final analysis including these 347 patients (median age 75 years, 56% women), prespecified test result categories incorporated 133 (38%) low APS, 162 (47%) high APS, and 52 (15%) intermediate APS patients. Clinicians' pretest and posttest AD diagnosis probability changed from 58% to 23% in low APS patients and 71% to 89% in high APS patients (p < 0.0001). Anti-AD drug therapy decreased by 46% in low APS patients (p < 0.0001) and increased by 57% in high APS patients (p < 0.0001). INTERPRETATION: These findings demonstrate the clinical utility of the PrecivityAD blood test in clinical care and may have added relevance as new AD therapies are introduced.

Independent study demonstrates amyloid probability score accurately indicates amyloid pathology.

BACKGROUND: The amyloid probability score (APS) is the model read-out of the analytically validated mass spectrometry-based PrecivityAD® blood test that incorporates the plasma Aß42/40 ratio, ApoE proteotype, and age to identify the likelihood of brain amyloid plaques among cognitively impaired individuals being evaluated for Alzheimer's disease. PURPOSE: This study aimed to provide additional independent evidence that the pre-established APS algorithm, along with its cutoff values, discriminates between amyloid positive and negative individuals. METHODS: The diagnostic performance of the PrecivityAD test was analyzed in a cohort of 200 nonrandomly selected Australian Imaging, Biomarker & Lifestyle Flagship Study of Aging (AIBL) study participants, who were either cognitively impaired or healthy controls, and for whom a blood sample and amyloid PET imaging were available. RESULTS: In a subset of the dataset aligned with the Intended Use population (patients aged 60 and older with CDR ≥0.5), the pre-established APS algorithm predicted amyloid PET with a sensitivity of 84.9% (CI: 72.9-92.1%) and specificity of 96% (CI: 80.5-99.3%), exclusive of 13 individuals for whom the test was inconclusive. INTERPRETATION: The study shows individuals with a high APS are more likely than those with a low APS to have abnormal amounts of amyloid plaques and be on an amyloid accumulation trajectory, a dynamic and evolving process characteristic of progressive AD pathology. Exploratory data suggest APS retains its diagnostic performance in healthy individuals, supporting further screening studies in the cognitively unimpaired.

Assessment of a Plasma Amyloid Probability Score to Estimate Amyloid Positron Emission Tomography Findings Among Adults With Cognitive Impairment.

Importance: The diagnostic evaluation for Alzheimer disease may be improved by a blood-based diagnostic test identifying presence of brain amyloid plaque pathology. Objective: To determine the clinical performance associated with a diagnostic algorithm incorporating plasma amyloid-ß (Aß) 42:40 ratio, patient age, and apoE proteotype to identify brain amyloid status. Design, Setting, and Participants: This cohort study includes analysis from 2 independent cross-sectional cohort studies: the discovery cohort of the Plasma Test for Amyloidosis Risk Screening (PARIS) study, a prospective add-on to the Imaging Dementia-Evidence for Amyloid Scanning study, including 249 patients from 2018 to 2019, and MissionAD, a dataset of 437 biobanked patient samples obtained at screenings during 2016 to 2019. Data were analyzed from May to November 2020. Exposures: Amyloid detected in blood and by positron emission tomography (PET) imaging. Main Outcomes and Measures: The main outcome was the diagnostic performance of plasma Aß42:40 ratio, together with apoE proteotype and age, for identifying amyloid PET status, assessed by accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). Results: All 686 participants (mean [SD] age 73.2 [6.3] years; 368 [53.6%] men; 378 participants [55.1%] with amyloid PET findings) had symptoms of mild cognitive impairment or mild dementia. The AUC of plasma Aß42:40 ratio for PARIS was 0.79 (95% CI, 0.73-0.85) and 0.86 (95% CI, 0.82-0.89) for MissionAD. Ratio cutoffs for Aß42:40 based on the Youden index were similar between cohorts (PARIS: 0.089; MissionAD: 0.092). A logistic regression model (LRM) incorporating Aß42:40 ratio, apoE proteotype, and age improved diagnostic performance within each cohort (PARIS: AUC, 0.86 [95% CI, 0.81-0.91]; MissionAD: AUC, 0.89 [95% CI, 0.86-0.92]), and overall accuracy was 78% (95% CI, 72%-83%) for PARIS and 83% (95% CI, 79%-86%) for MissionAD. The model developed on the prospectively collected samples from PARIS performed well on the MissionAD samples (AUC, 0.88 [95% CI, 0.84-0.91]; accuracy, 78% [95% CI, 74%-82%]). Training the LRM on combined cohorts yielded an AUC of 0.88 (95% CI, 0.85-0.91) and accuracy of 81% (95% CI, 78%-84%). The output of this LRM is the Amyloid Probability Score (APS). For clinical use, 2 APS cutoff values were established yielding 3 categories, with low, intermediate, and high likelihood of brain amyloid plaque pathology. Conclusions and Relevance: These findings suggest that this blood biomarker test could allow for distinguishing individuals with brain amyloid-positive PET findings from individuals with amyloid-negative PET findings and serve as an aid for Alzheimer disease diagnosis.

The PrecivityAD™ test: Accurate and reliable LC-MS/MS assays for quantifying plasma amyloid beta 40 and 42 and apolipoprotein E proteotype for the assessment of brain amyloidosis.

BACKGROUND: There is an unmet need for an accessible, less invasive, cost-effective method to facilitate clinical trial enrollment and aid in clinical Alzheimer's disease (AD) diagnosis. APOE genotype affects the clearance and deposition of amyloid-beta (Aß) with APOE4 carriers having increased risk while APOE2 alleles appear to be protective. Lower plasma Aß42/40 correlates with brain amyloidosis. In response, C2N has developed the PrecivityAD™ test; plasma LC-MS/MS assays for Aß isoform quantitation and qualitative APOE isoform-specific proteotyping. METHODS: In accord with CLIA standards, we developed and validated assay performance: precision, accuracy, linearity, limit of detection (LoD), interferences. RESULTS: Within-day precision varied from 1.5-3.0% (Aß40) and 2.5-8.4% (Aß42). Total (within-lab) variability was 2.7-7.7% (Aß40) and 3.1-9.5% (Aß42). Aß40 quantitation was linear from 10 to 1780 pg/mL; Aß42 was linear from 2 to 254 pg/mL. LoD was 11 and 2 pg/mL for Aß40 and Aß42, respectively. APOE proteotypes were 100% concordant with genotype, while LoD (fM) was much lower than APOE concentrations observed in plasma (mM). CONCLUSIONS: The PrecivityAD™ assays are precise, accurate, sensitive, and linear over a wide analytical range, free from significant interferences, and suitable for use in the clinical laboratory.

A blood-based diagnostic test incorporating plasma Aß42/40 ratio, ApoE proteotype, and age accurately identifies brain amyloid status: findings from a multi cohort validity analysis.

BACKGROUND: The development of blood-based biomarker tests that are accurate and robust for Alzheimer's disease (AD) pathology have the potential to aid clinical diagnosis and facilitate enrollment in AD drug trials. We developed a high-resolution mass spectrometry (MS)-based test that quantifies plasma Aß42 and Aß40 concentrations and identifies the ApoE proteotype. We evaluated robustness, clinical performance, and commercial viability of this MS biomarker assay for distinguishing brain amyloid status. METHODS: We used the novel MS assay to analyze 414 plasma samples that were collected, processed, and stored using site-specific protocols, from six independent US cohorts. We used receiver operating characteristic curve (ROC) analyses to assess assay performance and accuracy for predicting amyloid status (positive, negative, and standard uptake value ratio; SUVR). After plasma analysis, sites shared brain amyloid status, defined using diverse, site-specific methods and cutoff values; amyloid PET imaging using various tracers or CSF Aß42/40 ratio. RESULTS: Plasma Aß42/40 ratio was significantly (p < 0.001) lower in the amyloid positive vs. negative participants in each cohort. The area under the ROC curve (AUC-ROC) was 0.81 (95% CI = 0.77-0.85) and the percent agreement between plasma Aß42/40 and amyloid positivity was 75% at the optimal (Youden index) cutoff value. The AUC-ROC (0.86; 95% CI = 0.82-0.90) and accuracy (81%) for the plasma Aß42/40 ratio improved after controlling for cohort heterogeneity. The AUC-ROC (0.90; 95% CI = 0.87-0.93) and accuracy (86%) improved further when Aß42/40, ApoE4 copy number and participant age were included in the model. CONCLUSIONS: This mass spectrometry-based plasma biomarker test: has strong diagnostic performance; can accurately distinguish brain amyloid positive from amyloid negative individuals; may aid in the diagnostic evaluation process for Alzheimer's disease; and may enhance the efficiency of enrolling participants into Alzheimer's disease drug trials.

Race, medical researcher distrust, perceived harm, and willingness to participate in cardiovascular prevention trials.

Minority underrepresentation exists in medical research including cardiovascular clinical trials, but the hypothesis that this relates to distrust in medical researchers is unproven. Therefore, we examined whether African American persons differ from white persons in perceptions of the risks/benefits of trial participation and distrust toward medical researchers, and whether these factors influence willingness to participate (WTP) in a clinical drug trial. Participants were self-administered a survey regarding WTP in a cardiovascular drug trial given to 1440 randomly selected patients from 13 Maryland outpatient cardiology and general medicine clinics. Patients reported their WTP, rated their perceived chances of experiencing health benefit and harm, and rated their distrust toward researchers. Of eligible participants, 70% responded, and 717 individuals were included: 36% African American and 64% white. African American participants possessed lower WTP than white participants (27% vs. 39%, p = 0.001) and had higher mean distrust scores than whites (p < 0.0001). African American participants more frequently reported that doctors would less fully explain research participation to them (24% vs. 13%, p < 0.001), use them as guinea pigs without their consent (72% vs. 49%, p < 0.001), prescribe medication as a way of experimenting on people without their knowledge (35% vs. 16%, p < 0.001), and ask them to participate in research even if it could harm them (24% vs. 15%, p = 0.002). African American participants also more often believed they could less freely ask their doctor questions (8% vs. 2%, p < 0.001) and that doctors had previously experimented on them without their consent (58% vs. 25%, p < 0.001). African American participants expressed lesser WTP than white participants after controlling for racial differences in age, sex, socioeconomic status and cardiovascular disease risk profiles (multivariable odds ratio [OR], 0.57; 95% confidence interval [CI], 0.39-0.85). The impact of race was attenuated and nonsignificant after adjustment for potential mediating factors of racial differences in medical researcher distrust and perceived risk of harm (explanatory model OR, 0.84; 95% CI 0.54-1.30). In summary, African American participants expressed markedly greater concerns about experiencing harm from participation in clinical trials and distrust toward medical researchers than white participants. These factors, in turn, appear to explain much of the resistance among African American persons to participate in clinical trials compared to white persons.

Sex differences in perceived risks, distrust, and willingness to participate in clinical trials: a randomized study of cardiovascular prevention trials.

BACKGROUND: Multiple sex differences exist in cardiovascular disease burden and treatment efficacies; adequate participation of both sexes is crucial to clinical research. METHODS: A multicenter, double-blind, randomized study evaluated sex and trial scenarios on willingness to participate (WTP) in cardiovascular prevention trials and examined sex differences in perceived risks and distrust. Hypothetical trial scenarios randomized multifactorial vignettes of adverse effects, trial durations, sponsors, financial incentives, and conflicts of interest. RESULTS: With 783 participants across 13 clinical centers, women showed lower distrust of medical researchers, perceived greater risk of myocardial infarction, and perceived greater risk of harm from trial participation than men. Men had 15% greater WTP than women (33.1% vs 28.7%; relative risk [RR], 1.15; 95% confidence interval [CI], 1.02-1.31); adjusting for explanatory mediators, we found that sex differences in perceived risks and benefits explained the sex gap in WTP. Although greater perceived probability of harm (RR, 0.41; 95% CI, 0.23-0.72), health benefit (RR, 2.99; 95% CI, 1.63-5.46), and quality of care (RR, 1.71; 95% CI, 1.12-2.61) strongly predicted WTP (for perceived probabilities >or=80% vs <20%) similarly in both sexes, and perceptions of distrust and myocardial infarction risk predicted WTP differently between sexes (P

Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy.

Tauopathies are a group of disorders in which the cytosolic protein tau aggregates and accumulates in cells within the brain, resulting in neurodegeneration. A promising treatment being explored for tauopathies is passive immunization with anti-tau antibodies. We previously found that administration of an anti-tau antibody to human tau transgenic mice increased the concentration of plasma tau. We further explored the effects of administering an anti-tau antibody on plasma tau. After peripheral administration of an anti-tau antibody to human patients with tauopathy and to mice expressing human tau in the central nervous system, there was a dose-dependent increase in plasma tau. In mouse plasma, we found that tau had a short half-life of 8 min that increased to more than 3 hours after administration of anti-tau antibody. As tau transgenic mice accumulated insoluble tau in the brain, brain soluble and interstitial fluid tau decreased. Administration of anti-tau antibody to tau transgenic mice that had decreased brain soluble tau and interstitial fluid tau resulted in an increase in plasma tau, but this increase was less than that observed in tau transgenic mice without these brain changes. Tau transgenic mice subjected to acute neuronal injury using 3-nitropropionic acid showed increased interstitial fluid tau and plasma tau. These data suggest that peripheral administration of an anti-tau antibody results in increased plasma tau, which correlates with the concentration of extracellular and soluble tau in the brain.

Framingham risk equation underestimates subclinical atherosclerosis risk in asymptomatic women.

BACKGROUND: Coronary heart disease (CHD) is the leading cause of death among American women. Currently, global risk assessment derived by Framingham risk equation (FRE) is used to identify women at increased risk for CHD. Electron-beam computed tomography (EBCT) derived coronary artery calcium (CAC) scores are validated markers for future CHD events among asymptomatic individuals. However, the adequacy of FRE for identifying asymptomatic women with CAC is unknown. METHODS AND RESULTS: We studied 2447 consecutive non-diabetic asymptomatic females (55 +/- 10 years). Based upon FRE, 90% were classified as low-risk (FRE < or = 9% 10-year risk of hard CHD events), 10% intermediate-risk (10-20%), and none were considered as high-risk (> 20%). Coronary artery calcium was present in 33%, whereas CAC > or = 100 and CAC > or = 400 were seen in 10 and 3% of women, respectively. Overall, 20% of women had age-gender derived > or = 75th percentile CAC. According to FRE, the majority (84%) of women with significant CAC > or = 75th percentile were classified as low-risk. Approximately half (45%) of low-risk women with > or = 2 CHD risk factors and a family history of premature CHD had significant CAC. CONCLUSION: Framingham risk equation frequently classifies women as being low-risk, even in the presence of significant CAC. Determination of CAC may provide incremental value to FRE in identifying asymptomatic women who will benefit from targeted preventative measures.

Difference in atherosclerosis burden in different nations and continents assessed by coronary artery calcium.

We utilized coronary artery calcium scores (CACS) to assess differences in atherosclerosis burden between asymptomatic White populations living in continents with different cardiovascular disease rates. The similarities in the genetic pool between Brazilian and Portuguese Caucasian subjects offered an opportunity to assess the influence of environmental factors on the development of atherosclerosis. We reviewed CACS data from 17,563 individuals (12,378 men and 5169 women) collected in the USA (74% of the subjects), Brazil (15% of the subjects) and Portugal (11% of the subjects). CACS was absent in 80 and 88% of Portuguese men and women, compared with 46 and 62% and 33 and 59% of Brazilian and US counterparts (p<0.0001). Although the US subjects showed the lowest prevalence of risk factors they had a higher median (interquartile range) CACS than the Brazilian and the Portuguese cohorts: 4 (0;87), 1 (0;68) and 0 (0;0), respectively (p<0.0001). After adjusting for differences in age and cardiovascular risk factors, US men showed higher relative risk ratios of having any CACS than either Brazilian or Portuguese men. Brazilian and US women did not differ as far as risk of CACS although they demonstrated a greater risk than Portuguese women. In this study, significant differences in CACS were detected among three nations in different continents. The CACS differences paralleled the respective cardiovascular mortality rates.

The influence of health status, age, and race on screening mammography in elderly women.

BACKGROUND: Screening mammography is controversial for elderly women because of an absence of efficacy data. Decisions to screen are based on individualized assessment of risks and benefits. Our objective was to determine how screening mammography varies by age and race when adjusted for propensity to die. METHODS: In a retrospective cohort study, rates of screening mammogram performed in 2000-2001 based on claims, adjusted for propensity to die in 2000, were determined for a nationally representative 5% random sample of female fee-for-service Medicare beneficiaries 65 years and older in (N = 722,310). RESULTS: The overall rate of screening was 39%. When stratified into quintiles by propensity to die, 2-year rates ranged from 61% in the lowest-risk group to 5% in the highest-risk group. In analyses stratified by age and adjusted for propensity to die, 42% of women aged 65 to 69 years were screened, declining to 26% of women 85 years and older (P<.001). Adjusted screening rates for white women, black women, and women of other races were 40%, 30%, and 25%, respectively (P<.001). Thus, among women with similar health status, the youngest women were 1.61 times more likely to be screened compared with the oldest; compared with black women and women of other races, white women were 1.38 and 1.60 times, respectively, more likely to be screened. CONCLUSIONS: Decisions to screen for breast cancer are related not only to health status but also to age and race. Underuse and overuse of screening mammography likely occurs owing to age- and race-associated decision making. Assessment of life expectancy may more accurately identify women who could benefit from screening.

A randomized controlled study to evaluate the effect of bexarotene on amyloid-ß and apolipoprotein E metabolism in healthy subjects.

INTRODUCTION: We conducted a phase Ib proof of mechanism trial to determine whether bexarotene (Targretin) increases central nervous system (CNS) apolipoprotein E (apoE) levels and alters Aß metabolism in normal healthy individuals with the APOE ε3/ε3 genotype. METHODS: We used stable isotope labeling kinetics (SILK-ApoE and SILK-Aß) to measure the effect of bexarotene on the turnover rate of apoE and Aß peptides and stable isotope spike absolute quantitation (SISAQ) to quantitate their concentrations in the cerebrospinal fluid (CSF). Normal subjects were treated for 3 days with bexarotene (n = 3 women, 3 men, average 32 years old) or placebo (n = 6 women, average 30.2 years old) before administration of C13-leucine and collection of plasma and CSF over the next 48 hours. Bexarotene concentrations in plasma and CSF were also measured. RESULTS: Oral administration of bexarotene resulted in plasma levels of 1 to 2 µM; however, only low nM levels were found in CSF. Bexarotene increased CSF apoE by 25% but had no effect on metabolism of Aß peptides. DISCUSSION: Bexarotene has poor CNS penetration in normal human subjects. Drug treatment resulted in a modest increase in CSF apoE levels. The absence of an effect on Aß metabolism is likely reflective of the low CNS levels of bexarotene achieved. This study documents the utility of SILK-ApoE technology in measuring apoE kinetics in humans. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov (NCT02061878).

Coronary artery calcification and family history of premature coronary heart disease: sibling history is more strongly associated than parental history.

BACKGROUND: The objective of the study was to assess the association of a family history (FH) of premature coronary heart disease (CHD) with coronary artery calcification (CAC) in asymptomatic individuals and to compare the effects of sibling or parental FH on the risk of subclinical atherosclerosis. METHODS AND RESULTS: CAC by electron beam tomography was performed in 8549 asymptomatic individuals (69% men; mean age, 52+/-9 years). The prevalence and odds of any CAC and extent of CAC stratified according to FH of premature CHD were determined. Those with (1) no FH of CHD, (2) FH of premature CHD in parents, or (3) FH in siblings had a prevalence of CAC of 55%, 64%, and 78% (P<0.0001) among men and 27%, 36%, and 56% (P<0.0001) among women, respectively. The multivariate regression analysis demonstrated that the odds ratio (95% confidence interval) for the presence of CAC was 1.3 (1.1 to 1.6) among those with positive FH of premature CHD in parents only, 2.3 (1.7 to 3.1) and 2.5 (1.8 to 3.3) among those in siblings and a combined FH compared with those without FH of CHD in men, respectively. Among women, the corresponding odds ratios were 1.3 (1.0 to 1.8), 2.3 (1.7 to 3.6), and 1.9 (1.3 to 3.1), respectively. A similar trend was observed in the association of FH of premature CHD with increasing CAC scores. CONCLUSIONS: Our study demonstrates a highly significant association between FH of premature CHD and the presence and extent of CAC. Furthermore, within the limits of self-reporting of family history, our findings suggest that a sibling history is more strongly associated with subclinical coronary atherosclerosis than a parental history of premature CHD.

Noncardiac comorbidity increases preventable hospitalizations and mortality among Medicare beneficiaries with chronic heart failure.

OBJECTIVES: We studied the impact of noncardiac comorbidity on potentially preventable hospitalizations and mortality in elderly patients with chronic heart failure (CHF). BACKGROUND: Chronic HF disproportionately affects older individuals, who typically have extensive comorbidity. However, little is known about how noncardiac comorbidity complicates care in these patients. METHODS: This was a cross-sectional study of 122,630 individuals age >/=65 years with CHF identified through a 5% random sample of all U.S. Medicare beneficiaries. We assessed the relationship of the 20 most common noncardiac comorbidities to one-year potentially preventable hospitalizations and total mortality. Preventable hospitalizations were determined by admissions for ambulatory care sensitive conditions using predefined criteria. RESULTS: Sixty-five percent of the sample had at least one hospitalization, of which 50% were potentially preventable. Exacerbations of CHF accounted for 55% of potentially preventable hospitalizations. Nearly 40% of patients with CHF had >/=5 noncardiac comorbidities, and this group accounted for 81% of the total inpatient hospital days experienced by all CHF patients. The risk of hospitalization and potentially preventable hospitalization strongly increased with the number of chronic conditions (both p < 0.0001). After controlling for demographic factors and other diagnoses, comorbidities that were associated consistently with notably higher risks for CHF-preventable and all-cause preventable hospitalizations, and mortality, included chronic obstructive pulmonary disease/bronchiectasis, renal failure, diabetes, depression, and other lower respiratory diseases (all p < 0.01). CONCLUSIONS: Noncardiac comorbidities are highly prevalent in older patients with CHF and strongly associate with adverse clinical outcomes. Cardiologists and other providers routinely caring for older patients with CHF may improve outcomes in this high-risk population by better recognizing non-CHF conditions, which may complicate traditional CHF management strategies.