Secondary Prevention Trials Research Articles

Drug Development for Psychotropic, Cognitive-Enhancing, and Disease-Modifying Treatments for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited available therapies. There is progress in developing treatments for neuropsychiatric indications in AD, including agitation, psychosis, apathy, and sleep disorders. Candidate therapies progress from nonclinical and animal assessment to trials in normal volunteers (phase 1), small phase-2 trials, and larger confirmatory phase-3 trials. Biomarkers play an increasingly important role in selecting participants, stratifying populations, demonstrating target engagement, supporting disease modification, and monitoring safety. There are currently 121 agents in clinical trials, including treatments for neuropsychiatric symptoms, cognition enhancement, and disease progression. There are 27 agents in phase-1 trials, 65 in phase-2 trials, and 29 in phase-3 trials. Most of the agents in trials (80%) target disease modification. Treatments are being assessed in secondary prevention trials with cognitively normal individuals at high risk for the development of AD. There is progress in target diversification, trial designs, outcome measures, biomarkers, and trial population definitions that promise to accelerate developing new therapies for those with or at risk for AD.

A randomized controlled trial of brain and heart health manager-led mHealth secondary stroke prevention.

This study explores the effect of brain and heart health manager (BHHM)-led stroke secondary prevention on blood pressure, and in improving the self-management ability of stroke patients. The BHHM has not been reported. A total of 200 stroke patients, who were discharged from our hospital, were randomized into two groups at a 1:1 ratio: intervention group and control group. Patients in the control group were followed up for six months via telephone, while patients in the experimental group were followed up for six months using the BHHM-led mHealth follow-up. The primary outcomes were systolic blood pressure (BP) and self-management ability at 3, 6, 9 and 12 months, while the secondary outcomes included medication adherence, the body mass index (BMI), and blood low-density lipoprotein. The systolic BP between these two groups at four time points (Ftime =8.734, Fgroup =172.075, and Finteraction =11.363) was statistically significant (P<0.05). The self-health management ability at four time points during follow-up period (Ftime =115.09, Fgroup =1,185.50, and Finteraction =108.22) was also significantly different between these two groups. Furthermore, there was a statistically significant difference in compliance with medication at six months (χ2=37.616, P=0.000). However, after one year, there were no significant differences in BMI (t=0.214, P=0.644), total cholesterol (t=0.56, P=0.837), and low-density lipoprotein (t=0.042, P=0.455). The BHHM-led mHealth follow-up is an effective method for managing BP and improving the self-care ability. Furthermore, this approach has no obvious effect on the management of BMI and blood low-density lipoprotein. A potential signal of efficacy with the intervention was observed.

Reduction in saturated fat intake for cardiovascular disease.

Reducing saturated fat reduces serum cholesterol, but effects on other intermediate outcomes may be less clear. Additionally, it is unclear whether the energy from saturated fats eliminated from the diet are more helpfully replaced by polyunsaturated fats, monounsaturated fats, carbohydrate or protein. To assess the effect of reducing saturated fat intake and replacing it with carbohydrate (CHO), polyunsaturated (PUFA), monounsaturated fat (MUFA) and/or protein on mortality and cardiovascular morbidity, using all available randomised clinical trials. We updated our searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid) and Embase (Ovid) on 15 October 2019, and searched Clinicaltrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) on 17 October 2019. Included trials fulfilled the following criteria: 1) randomised; 2) intention to reduce saturated fat intake OR intention to alter dietary fats and achieving a reduction in saturated fat; 3) compared with higher saturated fat intake or usual diet; 4) not multifactorial; 5) in adult humans with or without cardiovascular disease (but not acutely ill, pregnant or breastfeeding); 6) intervention duration at least 24 months; 7) mortality or cardiovascular morbidity data available. Two review authors independently assessed inclusion, extracted study data and assessed risk of bias. We performed random-effects meta-analyses, meta-regression, subgrouping, sensitivity analyses, funnel plots and GRADE assessment. We included 15 randomised controlled trials (RCTs) (16 comparisons, 56,675 participants), that used a variety of interventions from providing all food to advice on reducing saturated fat. The included long-term trials suggested that reducing dietary saturated fat reduced the risk of combined cardiovascular events by 17% (risk ratio (RR) 0.83; 95% confidence interval (CI) 0.70 to 0.98, 12 trials, 53,758 participants of whom 8% had a cardiovascular event, I² = 67%, GRADE moderate-quality evidence). Meta-regression suggested that greater reductions in saturated fat (reflected in greater reductions in serum cholesterol) resulted in greater reductions in risk of CVD events, explaining most heterogeneity between trials. The number needed to treat for an additional beneficial outcome (NNTB) was 56 in primary prevention trials, so 56 people need to reduce their saturated fat intake for ~four years for one person to avoid experiencing a CVD event. In secondary prevention trials, the NNTB was 53. Subgrouping did not suggest significant differences between replacement of saturated fat calories with polyunsaturated fat or carbohydrate, and data on replacement with monounsaturated fat and protein was very limited. We found little or no effect of reducing saturated fat on all-cause mortality (RR 0.96; 95% CI 0.90 to 1.03; 11 trials, 55,858 participants) or cardiovascular mortality (RR 0.95; 95% CI 0.80 to 1.12, 10 trials, 53,421 participants), both with GRADE moderate-quality evidence. There was little or no effect of reducing saturated fats on non-fatal myocardial infarction (RR 0.97, 95% CI 0.87 to 1.07) or CHD mortality (RR 0.97, 95% CI 0.82 to 1.16, both low-quality evidence), but effects on total (fatal or non-fatal) myocardial infarction, stroke and CHD events (fatal or non-fatal) were all unclear as the evidence was of very low quality. There was little or no effect on cancer mortality, cancer diagnoses, diabetes diagnosis, HDL cholesterol, serum triglycerides or blood pressure, and small reductions in weight, serum total cholesterol, LDL cholesterol and BMI. There was no evidence of harmful effects of reducing saturated fat intakes. The findings of this updated review suggest that reducing saturated fat intake for at least two years causes a potentially important reduction in combined cardiovascular events. Replacing the energy from saturated fat with polyunsaturated fat or carbohydrate appear to be useful strategies, while effects of replacement with monounsaturated fat are unclear. The reduction in combined cardiovascular events resulting from reducing saturated fat did not alter by study duration, sex or baseline level of cardiovascular risk, but greater reduction in saturated fat caused greater reductions in cardiovascular events.

A Prehospital Acute Stroke Trial has Only Modest Impact on Enrollment in Concurrent, Post-arrival-Recruiting Stroke Trials

BackgroundBecause “time is brain,” acute stroke trials are migrating to the prehospital setting. The impact upon enrollment in post-arrival trials of earlier recruitment in a prehospital trial requires delineation. MethodsWe analyzed all patients recruited into acute and prevention stroke trials during an 8-year period when an academic medical center (AMC) was participating in a prehospital treatment trial – the NIH Field Administration of Stroke Treatment – Magnesium (FAST-MAG) study. ResultsDuring the study period, in addition to FAST-MAG, the AMC participated in 33 post-arrival stroke trials: 27 for acute cerebral ischemia, one for intracerebral hemorrhage, and 5 secondary prevention trials. Throughout the study period, the AMC was recruiting for at least 3 concurrent post-arrival acute trials. Among 199 patients enrolled in acute stroke trials, 98 (49%) were in FAST-MAG and 101 (51%) in concurrent, post-arrival acute trials. Among FAST-MAG patients, 67% were not eligible for any concurrent acute, post-arrival trial. Of 134 patients eligible for post-arrival acute trials, 101 (76%) were enrolled in post-arrival trials and 32 (24%) in FAST-MAG. Leading reasons FAST-MAG patients were ineligible for post-arrival acute trials were: NIHSS too low (23.4%), intracranial hemorrhage (17.9%), IV tPA used in standard management (9.0%), NIHSS too high (7.1%), and age too high (5.2%). ConclusionsA prehospital hyperacute stroke trial with wide entry criteria reduced only modestly, by one-fourth, enrollment into concurrently active, post-arrival stroke trials. Simultaneous performance of prehospital and post-arrival acute and secondary prevention stroke trials in research networks is feasible.

Cardiovascular prevention in the elderly: limitations and opportunities

The world's population is ageing; however, the prolonged life expectancy is barely associated with an increase of healthy aging, and an important part of this demographic shift is a rising susceptibility to development and progressive accumulation of multiple chronic illness, challenging healthcare systems. Aging, therefore, represents the major risk factor for multimorbidity, a milestone for progressive loss of resilience and age-related multisystem homeostatic dysregulation. Cardiovascular risk factors, time and comorbidities play a vicious role in the development of heart disease. Among the other comorbidities, age itself is one of the most important risk factors for the development of cardiovascular disease and the prevalence and incidence of cardiovascular disease in the elderly are significantly increased. Elderly subjects, particularly when frail and with comorbidities, however, are scarcely represented in primary and secondary prevention trial aimed to treat hypercholesterolemia, diabetes mellitus and arterial hypertension. In particular, concerns exist about whether treatment should more or less intensive according to tolerability and risk of interactions; as well as there is uncertainty about therapeutic targets at different ages.This article reviews the relationship between ageing and cardiovascular disease, focusing on several issues regarding cardiovascular prevention in the elderly.

Hypoperfusion Distal to Anterior Circulation Intracranial Atherosclerosis is Associated with Recurrent Stroke.

In patients with symptomatic vertebrobasilar intracranial atherosclerotic disease (ICAD), impaired distal flow predicts recurrent stroke, but limited data exist on the association between perfusion status and recurrent stroke in anterior circulation ICAD. This is a retrospective study of patients hospitalized for symptomatic ICAD with 50-99% stenosis of the intracranial carotid or middle cerebral artery. The primary outcome is recurrent symptomatic ischemic stroke in the territory of the artery with ≥50% stenosis within 90 days. The primary predictor is distal hypoperfusion on magnetic resonance (MR) or computed tomography (CT) perfusion, defined as a ≥15 mL volume of territory of the symptomatic artery with Tmax >6 seconds. Fifty patients met inclusion criteria, including 15 (30%) with recurrent stroke and 15 (30%) with distal hypoperfusion. Distal hypoperfusion was present in 10 of 15 (66.7%) with recurrent stroke versus 5 of 35 (14.3%) without recurrent stroke (P<.001). The hazard ratio for recurrent stroke in patients with distal hypoperfusion was 6.80 (95% confidence interval [CI] 2.31-20.0). Distal hypoperfusion in acutely symptomatic ICAD with 50-99% stenosis is associated with stroke recurrence. Distal hypoperfusion could be used to enrich future trials of secondary stroke prevention in ICAD patients.

Association Between Common Variants in RBFOX1, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease

Genetic studies of Alzheimer disease have focused on the clinical or pathologic diagnosis as the primary outcome, but little is known about the genetic basis of the preclinical phase of the disease. To examine the underlying genetic basis for brain amyloidosis in the preclinical phase of Alzheimer disease. In the first stage of this genetic association study, a meta-analysis was conducted using genetic and imaging data acquired from 6 multicenter cohort studies of healthy older individuals between 1994 and 2019: the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study, the Berkeley Aging Cohort Study, the Wisconsin Registry for Alzheimer's Prevention, the Biomarkers of Cognitive Decline Among Normal Individuals cohort, the Baltimore Longitudinal Study of Aging, and the Alzheimer Disease Neuroimaging Initiative, which included Alzheimer disease and mild cognitive impairment. The second stage was designed to validate genetic observations using pathologic and clinical data from the Religious Orders Study and Rush Memory and Aging Project. Participants older than 50 years with amyloid positron emission tomographic (PET) imaging data and DNA from the 6 cohorts were included. The largest cohort, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (n = 3154), was the PET screening cohort used for a secondary prevention trial designed to slow cognitive decline associated with brain amyloidosis. Six smaller, longitudinal cohort studies (n = 1160) provided additional amyloid PET imaging data with existing genetic data. The present study was conducted from March 29, 2019, to February 19, 2020. A genome-wide association study of PET imaging amyloid levels. From the 4314 analyzed participants (age, 52-96 years; 2478 participants [57%] were women), a novel locus for amyloidosis was noted within RBFOX1 (β = 0.61, P = 3 × 10-9) in addition to APOE. The RBFOX1 protein localized around plaques, and reduced expression of RBFOX1 was correlated with higher amyloid-β burden (β = -0.008, P = .002) and worse cognition (β = 0.007, P = .006) during life in the Religious Orders Study and Rush Memory and Aging Project cohort. RBFOX1 encodes a neuronal RNA-binding protein known to be expressed in neuronal tissues and may play a role in neuronal development. The findings of this study suggest that RBFOX1 is a novel locus that may be involved in the pathogenesis of Alzheimer disease.

Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients.

To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 μm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.

Examining Cognitive Decline Across Black and White Participants in the Harvard Aging Brain Study.

Black Americans are approximately twice as likely to develop dementia as compared to White Americans and the magnitude of this disparity is often attributed to a variety of factors that include psychosocial and vascular risk factors. However, less is known about the potential contribution of Alzheimer's disease pathological differences. To examine potential differences incross-sectional and longitudinal cognitive performance in black and white participants who were clinically normal at baseline. 296 participants (48 African-American/black participants) underwent MRI and amyloid PET at baseline. Linear mixed models were used to examine the main effects of race, years of education, reading ability, Framingham Heart Study cardiovascular risk score (FHS-CVD), white matter hyperintensities (WMH), and amyloid (Aβ) burden on the Preclinical Alzheimer Cognitive Composite-5 (PACC5). Lower levels of educationalattainment and reading ability were found for blacks compared to whites. By contrast, no differences in FHS-CVD, WMH, or Aβ were found by racial group. Baseline differences in PACC5 score were attenuated after adjusting for educationalfactors, vascular factors, and Aβ, but remained lower for blacks compared to whites (β= -0.24, p = 0.014). Further, blacks demonstrated a faster rate of PACC5 decline longitudinally compared to whites (β = -0.055, p = 0.025) after adjusting for covariates. Accounting for educationalfactors, vascular factors, and Aβ burden diminished, but did not eliminate, racial differences in PACC5 performance longitudinally. Understanding potential differences in longitudinal cognitive outcomes by race may be important for upcoming secondary prevention trials.

Impact of APOE-ε4 carriage on the onset and rates of neocortical Aβ-amyloid deposition

Neocortical Aβ-amyloid deposition, one of the hallmark pathologic features of Alzheimer's disease (AD), begins decades prior to the presence of clinical symptoms. As clinical trials move to secondary and even primary prevention, understanding the rates of neocortical Aβ-amyloid deposition and the age at which Aβ-amyloid deposition becomes abnormal is crucial for optimizing the timing of these trials. As APOE-ε4 carriage is thought to modulate the age of clinical onset, it is also important to understand the impact of APOE-ε4 carriage on the age at which the neocortical Aβ-amyloid deposition becomes abnormal. Here, we show that, for 455 participants with over 3 years of follow-up, abnormal levels of neocortical Aβ-amyloid were reached on average at age 72 (66.5–77.1). The APOE-ε4 carriers reached abnormal levels earlier at age 63 (59.6–70.3); however, noncarriers reached the threshold later at age 78 (76.1–84.4). No differences in the rates of deposition were observed between APOE-ε4 carriers and noncarriers after abnormal Aβ-amyloid levels had been reached. These results suggest that primary and secondary prevention trials, looking to recruit at the earliest stages of disease, should target APOE-ε4 carriers between the ages of 60 and 66 and noncarriers between the ages of 76 and 84.

Reduction in saturated fat intake for cardiovascular disease.

Reducing saturated fat reduces serum cholesterol, but effects on other intermediate outcomes may be less clear. Additionally, it is unclear whether the energy from saturated fats eliminated from the diet are more helpfully replaced by polyunsaturated fats, monounsaturated fats, carbohydrate or protein. To assess the effect of reducing saturated fat intake and replacing it with carbohydrate (CHO), polyunsaturated (PUFA), monounsaturated fat (MUFA) and/or protein on mortality and cardiovascular morbidity, using all available randomised clinical trials. We updated our searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid) and Embase (Ovid) on 15 October 2019, and searched Clinicaltrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) on 17 October 2019. Included trials fulfilled the following criteria: 1) randomised; 2) intention to reduce saturated fat intake OR intention to alter dietary fats and achieving a reduction in saturated fat; 3) compared with higher saturated fat intake or usual diet; 4) not multifactorial; 5) in adult humans with or without cardiovascular disease (but not acutely ill, pregnant or breastfeeding); 6) intervention duration at least 24 months; 7) mortality or cardiovascular morbidity data available. Two review authors independently assessed inclusion, extracted study data and assessed risk of bias. We performed random-effects meta-analyses, meta-regression, subgrouping, sensitivity analyses, funnel plots and GRADE assessment. We included 15 randomised controlled trials (RCTs) (16 comparisons, ~59,000 participants), that used a variety of interventions from providing all food to advice on reducing saturated fat. The included long-term trials suggested that reducing dietary saturated fat reduced the risk of combined cardiovascular events by 21% (risk ratio (RR) 0.79; 95% confidence interval (CI) 0.66 to 0.93, 11 trials, 53,300 participants of whom 8% had a cardiovascular event, I² = 65%, GRADE moderate-quality evidence). Meta-regression suggested that greater reductions in saturated fat (reflected in greater reductions in serum cholesterol) resulted in greater reductions in risk of CVD events, explaining most heterogeneity between trials. The number needed to treat for an additional beneficial outcome (NNTB) was 56 in primary prevention trials, so 56 people need to reduce their saturated fat intake for ~four years for one person to avoid experiencing a CVD event. In secondary prevention trials, the NNTB was 32. Subgrouping did not suggest significant differences between replacement of saturated fat calories with polyunsaturated fat or carbohydrate, and data on replacement with monounsaturated fat and protein was very limited. We found little or no effect of reducing saturated fat on all-cause mortality (RR 0.96; 95% CI 0.90 to 1.03; 11 trials, 55,858 participants) or cardiovascular mortality (RR 0.95; 95% CI 0.80 to 1.12, 10 trials, 53,421 participants), both with GRADE moderate-quality evidence. There was little or no effect of reducing saturated fats on non-fatal myocardial infarction (RR 0.97, 95% CI 0.87 to 1.07) or CHD mortality (RR 0.97, 95% CI 0.82 to 1.16, both low-quality evidence), but effects on total (fatal or non-fatal) myocardial infarction, stroke and CHD events (fatal or non-fatal) were all unclear as the evidence was of very low quality. There was little or no effect on cancer mortality, cancer diagnoses, diabetes diagnosis, HDL cholesterol, serum triglycerides or blood pressure, and small reductions in weight, serum total cholesterol, LDL cholesterol and BMI. There was no evidence of harmful effects of reducing saturated fat intakes. The findings of this updated review suggest that reducing saturated fat intake for at least two years causes a potentially important reduction in combined cardiovascular events. Replacing the energy from saturated fat with polyunsaturated fat or carbohydrate appear to be useful strategies, while effects of replacement with monounsaturated fat are unclear. The reduction in combined cardiovascular events resulting from reducing saturated fat did not alter by study duration, sex or baseline level of cardiovascular risk, but greater reduction in saturated fat caused greater reductions in cardiovascular events.

Prevention strategies for type 1 diabetes: a story of promising efforts and unmet expectations.

A number of studies have investigated primary and secondary prevention strategies for type 1 diabetes (T1D), since early interventions might improve long-term outcomes through the amelioration of immune processes and the preservation of beta-cell mass. Primary prevention trials focus on genetically at-risk individuals prior to the appearance of autoimmunity, whereas secondary prevention trials aim to halt the progression of complete beta-cell destruction in subjects with established islet autoimmunity (IA). Different approaches have been tested so far, focusing on both pharmaceutical (insulin and monoclonal antibodies) and non-pharmaceutical (vitamin D, omega-3 fatty acids, probiotics, and nicotinamide) interventions, as well as on environmental factors that are believed to trigger autoimmunity in T1D (cow's milk, gluten, and bovine insulin). Albeit certain strategies have displayed efficacy in reducing IA development rates, most efforts have been unsuccessful in preventing the onset of the disease in high-risk individuals. Moreover, significant heterogeneity in study designs, included populations, and explored outcomes renders the interpretation of study results challenging. The aim of this narrative review is to present and critically evaluate primary and secondary prevention strategies for T1D, seeking to fill existing knowledge gaps and providing insight into future directions.

Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Coronary Heart Disease (PROSPECTIVE).

Aims: Although intensive statin therapy reduced cardiovascular risks, cardiovascular events have not been completely prevented. Probucol is a potent antioxidant and reduces tendon xanthomas in familial hypercholesterolemia patients despite reduction of high-density lipoprotein (HDL)-cholesterol (HDL-C). We investigated whether probucol can reduce cardiovascular events on top of conventional lipid-lowering therapy in patients with coronary heart disease (CHD).Methods: PROSPECTIVE is a multicenter, randomized, prospective study that recruited 876 Japanese patients with CHD and dyslipidemia with a low-density lipoprotein (LDL)-cholesterol (LDL-C) level of ≥ 140 mg/dL without medication or those treated with lipid-lowering drugs. Lipid-lowering agents were administered during the study period in the control group (n = 438), and probucol 500 mg/day was added to lipid-lowering therapy in the probucol group (n = 438). Patients were randomly assigned to two treatment groups by adjusting the LDL-C level and presence of diabetes and hypertension and followed up for more than 3 years. The primary end point was a composite of cerebrovascular and cardiovascular events (cardiovascular disease death including sudden death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, hospitalization for heart failure, or coronary revascularization). The secondary end point was carotid intima-media thickness in a subset of patients.Results: The incidence of the primary end point showed a trend to be lower in the probucol group compared with that in the control group despite reduced HDL-C without serious adverse events. Anti-atherogenic effects of probucol may be attributed to its potent antioxidative function and enhancement of reverse cholesterol transport.Conclusion: Since there was no statistical significance between the probucol and control groups despite a marked reduction of HDL-C, further studies on the clinical outcomes of probucol on top of conventional therapy may be necessary in the future (UMIN000003307).

Association of Factors With Elevated Amyloid Burden in Clinically Normal Older Individuals

The Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) Study is an ongoing prevention trial in clinically normal older individuals with evidence of elevated brain amyloid. The large number of participants screened with amyloid positron emission tomography (PET) and standardized assessments provides an unprecedented opportunity to evaluate factors associated with elevated brain amyloid. To investigate the association of elevated amyloid with demographic and lifestyle factors, apolipoprotein E (APOE), neuropsychological testing, and self- and study partner reports of cognitive function. This cross-sectional study included screening data in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study collected from April 2014 to December 2017 and classified by amyloid status. Data were was analyzed from 2018 to 2019 across 67 sites in the US, Canada, Australia, and Japan and included 4486 older individuals (age 65-85 years) who were eligible for amyloid PET (clinically normal [Clinical Dementia Rating = 0] and cognitively unimpaired [Mini-Mental State Examination score, ≥25; logical memory IIa 6-18]). Screening demographics, lifestyle variables, APOE genotyping, and cognitive testing (Preclinical Alzheimer Cognitive Composite), self- and study partner reports of high-level daily cognitive function (Cognitive Function Index). Florbetapir amyloid PET imaging was used to classify participants as having elevated amyloid (Aβ+) or not having elevated amyloid (Aβ-). Amyloid PET results were acquired for 4486 participants (mean [SD] age, 71.29 [4.67] years; 2647 women [59%]), with 1323 (29.5%) classified as Aβ+. Aβ+ participants were slightly older than Aβ-, with no observed differences in sex, education, marital or retirement status, or any self-reported lifestyle factors. Aβ+ participants were more likely to have a family history of dementia (3320 Aβ+ [74%] vs 3050 Aβ- [68%]) and at least 1 APOE ε4 allele (2602 Aβ+ [58%] vs 1122 Aβ- [25%]). Aβ+ participants demonstrated worse performance on screening Preclinical Alzheimer Cognitive Composite results and reported higher change scores on the Cognitive Function Index. Among a large group of older individuals screening for an Alzheimer disease (AD) prevention trial, elevated brain amyloid was associated with family history and APOE ε4 allele but not with multiple other previously reported risk factors for AD. Elevated amyloid was associated with lower test performance results and increased reports of subtle recent declines in daily cognitive function. These results support the hypothesis that elevated amyloid represents an early stage in the Alzheimer continuum and demonstrate the feasibility of enrolling these high-risk participants in secondary prevention trials aimed at slowing cognitive decline during the preclinical stages of AD.

Amyloid β-protein and beyond: the path forward in Alzheimer's disease.

Basic research on the biological mechanism of Alzheimer's disease has focused for decades on the age-related aggregation of the amyloid β-protein and its apparent downstream effects on microglia, astrocytes and neurons, including the posttranslational modification of the tau protein that seems necessary for symptom expression. Here, we discuss the highly challenging process of developing disease-modifying therapies and highlight several key areas of current research that are progressing in exciting directions. We conclude that further deep molecular analyses of the disease, including the mechanisms of β-amyloidosis, will enable more effective clinical trials and ultimately achieve the progress that our patients so deserve.

Abstract WMP95: Sociodemographic Factors Associated With Retention of Minorities: Findings From the Secondary Stroke Prevention by Uniting Community and Chronic Care Model Teams Early to End Disparities (SUCCEED) Trial

Background: Minority and socioeconomically disadvantaged individuals are underrepresented in secondary stroke prevention trials. Little is known about factors associated with study retention in these populations. Objective: To evaluate the impact of sociodemographic characteristics on retention in the Secondary stroke prevention by Uniting Community and Chronic care model teams Early to End Disparities (SUCCEED) trial. Methods: 487 participants ≥40 years with stroke/TIA were recruited from 4 safety-net hospitals and 1 stroke center serving low income zip codes. Strategies for boosting retention included: having bilingual research assistants from similar cultures establish rapport and follow participants; culturally and linguistically tailoring materials; arranging visits around participants’ schedules; offering transportation, and conducting assessments in the home and community. We compared sociodemographic characteristics among those retained at 12 months (n=412) vs. those not retained (n=75) using t-test, Chi Square, and Fisher exact tests. Independent factors associated with retention were determined using logistic regression. Results: Average age was 57 years, 18% were black, 71% were Hispanic, 58% were Spanish-speaking, and 72% were born outside the US. 12-month retention was 85%. On bivariate analysis, factors associated with retention were: Spanish-speaking, Hispanic ethnicity, younger age, born outside the US, and married status (all p&lt;0.05). After multivariate analysis, study site, younger age (&lt;64 vs ≥65 years OR 2.2, 95% CI 1.1,4.4), married status (OR 2.0, 1.0,4.2), government insurance (vs uninsured OR 25.1, 1.2,5.1), private insurance (vs uninsured, OR 4.6, 1.3,16.4), and inability to afford medical care (OR 2.9, 1.3,6.7) were associated with retention. Discussion: In this secondary prevention trial of stroke survivors from predominantly minority backgrounds, younger age, marriage, and insurance were associated with retention, suggesting that addressing barriers in the elderly, and those without insurance or spousal support may be beneficial. Financial constraints were associated with retention suggesting that study participation appealed to more socioeconomically vulnerable individuals.

Prescreening for European Prevention of Alzheimer Dementia (EPAD) trial-ready cohort: impact of AD risk factors and recruitment settings

BackgroundRecruitment is often a bottleneck in secondary prevention trials in Alzheimer disease (AD). Furthermore, screen-failure rates in these trials are typically high due to relatively low prevalence of AD pathology in individuals without dementia, especially among cognitively unimpaired. Prescreening on AD risk factors may facilitate recruitment, but the efficiency will depend on how these factors link to participation rates and AD pathology. We investigated whether common AD-related factors predict trial-ready cohort participation and amyloid status across different prescreen settings.MethodsWe monitored the prescreening in four cohorts linked to the European Prevention of Alzheimer Dementia (EPAD) Registry (n = 16,877; mean ± SD age = 64 ± 8 years). These included a clinical cohort, a research in-person cohort, a research online cohort, and a population-based cohort. Individuals were asked to participate in the EPAD longitudinal cohort study (EPAD-LCS), which serves as a trial-ready cohort for secondary prevention trials. Amyloid positivity was measured in cerebrospinal fluid as part of the EPAD-LCS assessment. We calculated participation rates and numbers needed to prescreen (NNPS) per participant that was amyloid-positive. We tested if age, sex, education level, APOE status, family history for dementia, memory complaints or memory scores, previously collected in these cohorts, could predict participation and amyloid status.ResultsA total of 2595 participants were contacted for participation in the EPAD-LCS. Participation rates varied by setting between 3 and 59%. The NNPS were 6.9 (clinical cohort), 7.5 (research in-person cohort), 8.4 (research online cohort), and 88.5 (population-based cohort). Participation in the EPAD-LCS (n = 413 (16%)) was associated with lower age (odds ratio (OR) age = 0.97 [0.95–0.99]), high education (OR = 1.64 [1.23–2.17]), male sex (OR = 1.56 [1.19–2.04]), and positive family history of dementia (OR = 1.66 [1.19–2.31]). Among participants in the EPAD-LCS, amyloid positivity (33%) was associated with higher age (OR = 1.06 [1.02–1.10]) and APOE ɛ4 allele carriership (OR = 2.99 [1.81–4.94]). These results were similar across prescreen settings.ConclusionsNumbers needed to prescreen varied greatly between settings. Understanding how common AD risk factors link to study participation and amyloid positivity is informative for recruitment strategy of studies on secondary prevention of AD.

The Computerized Cognitive Composite (C3) in A4, an Alzheimer\u2019s Disease Secondary Prevention Trial

BackgroundComputerized cognitive assessments may improve Alzheimer’s disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers.ObjectiveTo assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3).DesignCross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD).SettingMulti-center international study.ParticipantsClinically normal (CN) older adults (65–85; n=4486)MeasurementsParticipants underwent florbetapir-Positron Emission Tomography for Aβ+/− classification. They completed the C3 and standard paper and pencil measures included in the Preclinical Alzheimer’s Cognitive Composite (PACC). The C3 combines memory measures sensitive to change over time (Cogstate Brief Battery-One Card Learning) and measures shown to be declining early in AD including pattern separation (Behavioral Pattern Separation Test- Object-Lure Discrimination Index) and associative memory (Face Name Associative Memory Exam- Face-Name Matching). C3 acceptability and completion rates were assessed using qualitative and quantitative methods. C3 performance was explored in relation to Aβ+/− groups (n=1323/3163) and PACC.ResultsC3 was feasible for CN older adults to complete. Rates of incomplete or invalid administrations were extremely low, even in the bottom quartile of cognitive performers (PACC). C3 was moderately correlated with PACC (r=0.39). Aβ+ performed worse on C3 compared with Aβ− [unadjusted Cohen’s d=−0.22 (95%CI: −0.31,−0.13) p<0.001] and at a magnitude comparable to the PACC [d=−0.32 (95%CI: −0.41,−0.23) p<0.001]. Better C3 performance was observed in younger, more educated, and female participants.ConclusionsThese findings provide support for both the feasibility and validity of C3 and computerized cognitive outcomes more generally in AD secondary prevention trials.

Device Therapy for Sudden Cardiac Death Prophylaxis After Acute Coronary Syndrome: When and Why?

Implantable cardioverter-defibrillators (ICDs) are a powerful tool in preventing sudden cardiac death due to ventricular arrhythmias in ischemic cardiomyopathy. ICD indications and timing in acute coronary syndromes are unclear. PURPOSE OF REVIEW: We reviewed several trials that delineated the indications for a cardiac defibrillator in patients with coronary artery disease. RECENT FINDINGS: The role of cardiac defibrillators in secondary prevention has been well established by AVID, CIDS, and CASH trials. AVID showed reduction in both all-cause mortality and arrhythmic death while the two smaller trials showed only improvement in arrhythmic death. Similarly, trials like MADIT, CABG Patch, MUSTT, MADIT-II, DINAMIT, and the IRIS trial have fine-tuned the indications for ICD in primary prevention of sudden cardiac death. Benefits of an ICD were most pronounced in those with reduced ejection fraction and 40days or more since myocardial infarction or in those who were not immediately post revascularization. The recent VEST trial aimed to study wearable cardioverter-defibrillators (WCDs) in patients who did not have an indication for an implantable defibrillator. The arrhythmic deaths (1.6% vs. 2.4%) were not reduced by the WCD. Based on consistent reduction in arrhythmic death in all primary and secondary prevention trials, defibrillators are effective in carefully selected patients.

The Role of Clinical Trials in Preclinical Alzheimer\u2019s Disease Drug Development Programs

Alzheimer’s disease (AD) has a 15-20 year preclinical phase during which the individuals have normal cognition by conventional measures and have state measures of AD pathology including elevated levels of brain amyloid when assessed with positron emission tomography (PET) and abnormally decreased levels cerebrospinal fluid (CSF) amyloid beta-protein (Aß) and increased levels of total tau and hyperphosphorylated tau (p-tau) (1, 2). Recognition of this long-preclinical phase and the presence of biomarker changes affords, the opportunity to plan secondary prevention trials to prevent or delay the onset of cognitive impairment and progression to dementia. The US Food and Drug Administration (FDA) facilitated planning of clinical trials for participants in the preclinical phase of AD by defining two stages of the preclinical period: in stage 1 participants have characteristic pathophysiologic changes of AD but no evidence of clinical impact; in stage 2 participants have characteristic pathophysiologic changes of AD and subtle detectable abnormalities on sensitive neuropsychological measures, but no functional impairment. Stage 3 participants are no longer in the preclinical phase of AD; they have mild cognitive impairment (MCI)/prodromal AD with characteristic pathophysiologic changes of AD, subtle or more apparent detectable abnormalities on sensitive neuropsychological measures, and mild but detectable functional impairment. Stages 4, 5, and 6 describe patients with mild, moderate and severe AD dementia. Biomarker, clinical definitions, and regulatory engagement have set the stage for planning and conduct of trials in preclinical AD.