Immediate Reactions to Alzheimer Biomarker Disclosure in Cognitively Unimpaired Individuals in a Global Truncated Randomized Trial.

Background and Objectives: Preclinical Alzheimer disease (AD) trials simultaneously test candidate treatments and the implications of disclosing biomarker information to cognitively unimpaired individuals. Methods: The EARLY trial was a randomized, double-blind, placebo-controlled, phase 2b/3 study conducted in 143 centers across 14 countries from November 2015 to December 2018 after being stopped prematurely because of treatment-related hepatotoxicity. Participants age 60-85 years deemed cognitively unimpaired were disclosed an elevated or not elevated brain amyloid result by a certified clinician. Among 3,686 participants, 2,066 underwent amyloid imaging, 1,394 underwent CSF biomarker assessment, and 226 underwent both. Among biomarker-tested participants with at least one change score on an outcome of interest, 680 with elevated and 2,698 with not elevated amyloid were included in this analysis. We compared the Geriatric Depression Scale (GDS), the State-Trait Anxiety Scale (STAI), and the Columbia Suicide Severity Rating Scale (CSSRS) before disclosure between amyloid groups. After disclosure, we assessed for differences in the Impact of Events Scale (IES, collected 24-72 hours after disclosure), a measure of intrusive thoughts. Additional scales included the Concerns for AD scale. Results: Among 3378 included participants, the mean (SD) age was 69.0 (5.3); most were female (60%) and White race (84%). No differences were observed before disclosure between participants with elevated and not elevated amyloid for the GDS, STAI, or CSSRS. Participants with elevated amyloid demonstrated higher Concerns for AD scores compared with participants with not elevated amyloid before disclosure. Participants with elevated amyloid demonstrated higher IES scores (9.6 [10.8] vs 5.1 [8.0]) after disclosure and increased Concerns about AD. Patterns of reactions (elevated vs not elevated) were similar for biomarker modalities, although scores were lower among those undergoing CSF compared with PET testing. Although score differences were apparent comparing geographical regions, patterns of group differences were similar. Discussion: Although sample bias must be considered, these results suggest that amyloid disclosure resulted in increased perceived risk and mild distress in those learning an elevated result. Although this study did not assess psychological safety, observed associations intrusive thoughts and distress could be important considerations in the future clinical practice.

Eligibility Rates among Racially and Ethnically Diverse US Participants in Phase 2 and Phase 3 Placebo-Controlled, Double-Blind, Randomized Trials of Lecanemab and Elenbecestat in Early Alzheimer Disease.

OBJECTIVE: Many factors contribute to inadequate diversity in Alzheimer disease (AD) clinical trials. We evaluated eligibility rates among racial and ethnic groups at US sites in large global multisite trials in early AD. METHODS: Using screening data from 4 randomized, double-blind, placebo-controlled clinical trials in early AD, we assessed rates of eligibility among racial and ethnic groups controlling for other demographic covariates. Each trial incorporated positron emission tomography and/or cerebrospinal fluid to evaluate brain amyloid pathology, as well as typical eligibility criteria used in early AD trials. RESULTS: Across the trials, 10,804 US participants were screened: 193 (2%) were of Hispanic ethnicity and Black race, 2,624 (25%) were of Hispanic ethnicity and White race, 118 (1%) were of non-Hispanic ethnicity (NH) and Asian race, 696 (7%) were of NH ethnicity and Black race, and 7,017 (65%) were of NH ethnicity and White race. Data from 156 participants who did not fit into these categories were excluded. Accounting for age, sex, and trial and using NH White participants as a reference group, we observed higher probabilities of ineligibility for amyloid biomarker criteria among Hispanic Black (odds ratio [OR] = 3.20, 95% confidence interval [CI] = 2.11-4.88), Hispanic White (OR = 4.15, 95% CI = 3.58-4.83), NH Asian (OR = 2.35, 95% CI = 1.23-4.55), and NH Black (OR = 3.75, 95% CI = 2.80-5.06) participants. INTERPRETATION: Differential eligibility may contribute to underrepresentation of some minoritized racial and ethnic groups in early AD trials. Amyloid biomarker eligibility is a requirement to confirm the diagnosis of AD and for treatment with amyloid-lowering drugs and differed among racial and ethnic groups. ANN NEUROL 2024;95:288-298.

Centralizing prescreening data collection to inform data-driven approaches to clinical trial recruitment.

BACKGROUND: Recruiting to multi-site trials is challenging, particularly when striving to ensure the randomized sample is demographically representative of the larger disease-suffering population. While previous studies have reported disparities by race and ethnicity in enrollment and randomization, they have not typically investigated whether disparities exist in the recruitment process prior to consent. To identify participants most likely to be eligible for a trial, study sites frequently include a prescreening process, generally conducted by telephone, to conserve resources. Collection and analysis of such prescreening data across sites could provide valuable information to improve understanding of recruitment intervention effectiveness, including whether traditionally underrepresented participants are lost prior to screening. METHODS: We developed an infrastructure within the National Institute on Aging (NIA) Alzheimer's Clinical Trials Consortium (ACTC) to centrally collect a subset of prescreening variables. Prior to study-wide implementation in the AHEAD 3-45 study (NCT NCT04468659), an ongoing ACTC trial recruiting older cognitively unimpaired participants, we completed a vanguard phase with seven study sites. Variables collected included age, self-reported sex, self-reported race, self-reported ethnicity, self-reported education, self-reported occupation, zip code, recruitment source, prescreening eligibility status, reason for prescreen ineligibility, and the AHEAD 3-45 participant ID for those who continued to an in-person screening visit after study enrollment. RESULTS: Each of the sites was able to submit prescreening data. Vanguard sites provided prescreening data on a total of 1029 participants. The total number of prescreened participants varied widely among sites (range 3-611), with the differences driven mainly by the time to receive site approval for the main study. Key learnings instructed design/informatic/procedural changes prior to study-wide launch. CONCLUSION: Centralized capture of prescreening data in multi-site clinical trials is feasible. Identifying and quantifying the impact of central and site recruitment activities, prior to participants signing consent, has the potential to identify and address selection bias, instruct resource use, contribute to effective trial design, and accelerate trial enrollment timelines.

Attitudes about involvement in hypothetical clinical trial protocols in Mexican and Mexican-American at risk for autosomal dominant Alzheimer's disease.

BACKGROUND: The enrollment into clinical trials of persons at risk for autosomal dominant Alzheimer's disease (ADAD) in whom the onset of disease can be accurately predicted facilitates the interpretation of outcomes (e.g., biomarkers, treatment efficacy). Attitudes toward involvement in such studies are biased by intrinsic cultural and social characteristics. Our objective was to study how demographic factors such as country of residence, age, sex, schooling, parenthood, and urbanization affect attitudes towards participation in hypothetical clinical trials in Mexican families at risk for ADAD living either in Mexico or in the United States. METHODS: Participants were 74 members of different families known to harbor an ADAD mutation living in Mexico (n = 50) or in the United States (n = 24). Participants were asked, in a written questionnaire, their interest in participating in four hypothetical clinical trial scenarios of increasing perceived invasiveness. The questionnaire then asked about their willingness should there be a 50% chance of being assigned to a placebo group. The influences of demographic variables on decisions were performed using Wilcoxon rank-sum for continuous variables and Fisher's exact test for categorical variables. RESULTS: Participants who live in Mexico, who have or plan to have children, who do not attend or do not plan to attend school, and who live in rural areas gave more positive responses regarding their willingness to participate compared to those living in the U.S. The 50% chance of being in a placebo group increased the willingness to participate for family members living in Mexico. The main reason for participation was to help future generations, while the main reasons for refusal were not wanting to undergo genetic testing and consideration of adverse effects. CONCLUSIONS: We found a higher level of willingness to participate in clinical trials among persons living in rural Mexico and our data suggest that altruism towards future generations is a major motivation, though this was balanced against concerns regarding side effects. Our results emphasize the importance of sharing information and assessing its understanding in potential participants with diverse backgrounds in the nature of ADAD and regarding the design of clinical trials prior to their enrollment in such studies.

Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial.

Importance: Atabecestat, a nonselective oral ß-secretase inhibitor, was evaluated in the EARLY trial for slowing cognitive decline in participants with preclinical Alzheimer disease. Preliminary analyses suggested dose-related cognitive worsening and neuropsychiatric adverse events (AEs). Objective: To report efficacy, safety, and biomarker findings in the EARLY trial, both on and off atabecestat treatment, with focus on potential recovery of effects on cognition and behavior. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 2b/3 study conducted from November 2015 to December 2018 after being stopped prematurely. The study was conducted at 143 centers across 14 countries. Participants were permitted to be followed off-treatment by the original protocol, collecting safety and efficacy data. From 4464 screened participants, 557 amyloid-positive, cognitively normal (Clinical Dementia Rating of 0; aged 60-85 years) participants (approximately 34% of originally planned 1650) were randomized before the trial sponsor stopped enrollment. Interventions: Participants were randomized (1:1:1) to atabecestat, 5 mg (n = 189), 25 mg (n = 183), or placebo (n = 185). Main Outcomes and Measures: Primary outcome: change from baseline in Preclinical Alzheimer Cognitive Composite score. Secondary outcomes: change from baseline in the Cognitive Function Index and the Repeatable Battery for the Assessment of Neuropsychological Status total scale score. Safety was monitored throughout the study. Results: Of 557 participants, 341 were women (61.2%); mean (SD) age was 70.4 (5.56) years. In May 2018, study medication was stopped early owing to hepatic-related AEs; participants were followed up off-treatment for 6 months. Atabecestat, 25 mg, showed significant cognitive worsening vs placebo for Preclinical Alzheimer Cognitive Composite at month 6 (least-square mean difference, -1.09; 95% CI, -1.66 to -0.53; P < .001) and month 12 (least-square mean, -1.62; 95% CI, -2.49 to -0.76; P < .001), and at month 3 for Repeatable Battery for the Assessment of Neuropsychological Status (least-square mean, -3.70; 95% CI, -5.76 to -1.63; P < .001). Cognitive Function Index participant report showed nonsignificant worsening at month 12. Systemic and neuropsychiatric-related treatment-emergent AEs were greater in atabecestat groups vs placebo. After stopping treatment, follow-up cognitive testing and AE assessment provided evidence of reversibility of drug-induced cognitive worsening and AEs in atabecestat groups. Conclusions and Relevance: Atabecestat treatment was associated with dose-related cognitive worsening as early as 3 months and presence of neuropsychiatric treatment-emergent AEs, with evidence of reversibility after 6 months off treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02569398.

Short-term Psychological Outcomes of Disclosing Amyloid Imaging Results to Research Participants Who Do Not Have Cognitive Impairment.

Importance: The goal of preclinical Alzheimer disease (AD) clinical trials is to move diagnosis and treatment to presymptomatic stages, which will require biomarker testing and disclosure. Objective: To assess the short-term psychological outcomes of disclosing amyloid positron emission tomography results to older adults who did not have cognitive impairment. Design, Setting, and Participants: This observational study included participants who were screening for a multisite randomized clinical trial that began on February 28, 2014, and is anticipated to be completed in 2022. Participants aged 65 to 85 years who had no known cognitive impairments underwent an amyloid positron emission tomography scan and learned their result from an investigator who used a protocol-specified process that included prescan education and psychological assessments. This report compares participants with elevated amyloid levels with at least 1 available outcome measure with participants who did not have elevated amyloid levels who enrolled in an observational cohort study and received further evaluations. Data were collected from April 2014 to December 2017 and analyzed from March 2019 to October 2019. Exposures: A personal biomarker result described as either an elevated or not elevated amyloid level. Main Outcomes and Measures: To assess the immediate and short-term psychological outcome of disclosure, the following validated measures were used: the Geriatric Depression Scale, the state items from the State-Trait Anxiety Inventory, and the Columbia Suicide Severity Rating Scale, as well as the Concerns About AD Scale and the Future Time Perspective Scale to assess changes in participants' perceived risk for AD and perceived remaining life span, respectively. Results: A total of 1167 participants with elevated amyloid levels and 538 participants with not elevated amyloid levels were included. Participants had a mean (SD) age of 71.5 (4.7) years, 1025 (60.1%) were women, and most were white (1611 [94.5%]) and non-Latino (1638 [96.1%]). Compared with participants who learned that they had a not elevated amyloid result, individuals who learned of an elevated amyloid result were no more likely to experience short-term increases in depression (mean [SD] change in the Geriatric Depression Scale score, 0.02 [1.3] vs 0.04 [1.3]; P = .90), anxiety (mean [SD] change in State-Trait Anxiety Inventory score, -0.02 [3.2] vs -0.15 [3.0]; P = .65), or suicidality (mean [SD] change in the Columbia Suicide Severity Rating Scale score, 0.0 [0.4] vs -0.01 [0.5]; P = .67). Participants with elevated amyloid levels had increased Concern About AD scores (raw change in scores: elevated amyloid group, 0.8 [3.9]; not elevated amyloid group, -0.4 [3.8]; P < .001). Participants with not elevated amyloid levels experienced a slight increase in Future Time Perspective score(mean [SD] score, 1.15 [7.4] points; P < .001); there was no change in time perspective among those receiving an elevated amyloid result (mean [SD] score, 0.33 [7.8] points). Conclusions and Relevance: In this observational preclinical AD study, participants who learned they had elevated amyloid levels did not experience short-term negative psychological sequelae compared with persons who learned they did not have elevated amyloid levels.

Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: There are no US Food and Drug Administration-approved therapies for neonatal seizures. Phenobarbital and phenytoin frequently fail to control seizures. There are concerns about the safety of seizure medications in the developing brain. Levetiracetam has proven efficacy and an excellent safety profile in older patients; therefore, there is great interest in its use in neonates. However, randomized studies have not been performed. Our objectives were to study the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment of neonatal seizures. METHODS: The study was a multicenter, randomized, blinded, controlled, phase IIb trial investigating the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment for neonatal seizures of any cause. The primary outcome measure was complete seizure freedom for 24 hours, assessed by independent review of the EEGs by 2 neurophysiologists. RESULTS: Eighty percent of patients (24 of 30) randomly assigned to phenobarbital remained seizure free for 24 hours, compared with 28% of patients (15 of 53) randomly assigned to levetiracetam (P < .001; relative risk 0.35 [95% confidence interval: 0.22-0.56]; modified intention-to-treat population). A 7.5% improvement in efficacy was achieved with a dose escalation of levetiracetam from 40 to 60 mg/kg. More adverse effects were seen in subjects randomly assigned to phenobarbital (not statistically significant). CONCLUSIONS: In this phase IIb study, phenobarbital was more effective than levetiracetam for the treatment of neonatal seizures. Higher rates of adverse effects were seen with phenobarbital treatment. Higher-dose studies of levetiracetam are warranted, and definitive studies with long-term outcome measures are needed.

Tobacco use and E-cigarette regulation: Perspectives of University Students in the Asia-Pacific.

INTRODUCTION: The Asia-Pacific is home to 30% of the world's smokers. Additional efforts are needed to reduce negative health impacts of tobacco, including e-cigarettes. The study objectives were to 1. Investigate Asian-Pacific students' knowledge, attitudes, and use of tobacco products; 2. Determine the level of student support for tobacco control policies; and 3. Examine differences in students' attitudes by the strength of national tobacco control policies based on implementation of WHO's MPOWER package, and e-cigarette regulation in their countries. METHODS: A total of 1953 students from members of the Association of Pacific Rim Universities in 13 countries completed the online survey. We compared the results by the Fisher-Freeman-Halton test. RESULTS: While about 83% of students had heard of e-cigarettes; only 14.1% had tried them. Students in countries with e-cigarette bans were the least likely to report having experimented with e-cigarettes (8.1%). While the vast majority of students (87.9%) reported having seen health campaigns targeting combustible cigarettes, far fewer (42.5%) had seen any health campaigns targeting e-cigarettes. About 80% of students supported smoke-free campuses, with the most support coming from those in countries with the weakest adoption of MPOWER policies (88.7%) and no e-cigarette regulations (80.4%). Students in countries with the weakest MPOWER policies were also the most likely to support campus bans and government regulation of e-cigarettes. CONCLUSIONS: The adoption of tobacco control polices by government may have an impact on e-cigarette smoking behavior among students, and student support for tobacco control, including noncombustible products, is high. Universities should take action by adopting comprehensive tobacco control measures that include e-cigarette regulations.

A mixed-methods study of cultural beliefs about dementia and genetic testing among Mexicans and Mexican-Americans at-risk for autosomal dominant Alzheimer's disease.

Trials to prevent autosomal dominantly inherited Alzheimer's disease (ADAD) are critical and timely. However, cultural beliefs about AD and genetic testing may preclude informed consent and participation, especially among racial/ethnic minorities. This mixed-methods study examines cultural beliefs about AD and genetic screening among at-risk populations of Mexican heritage. We surveyed 86 Mexican and 37 Mexican-American family members of patients with ADAD and interviewed 18 respondents in Mexico to explore perceptions and knowledge regarding AD and genetic testing. While most respondents understood that AD is inherited in their families, they also had limited understanding of the genetic mechanisms behind AD. Many believed that AD is a normal part of aging or that it is a mental illness caused by bad habits. However, beliefs that AD is caused by a curse or God's will were uncommon. The interviews demonstrated that very few at-risk respondents understood their own risk for harboring the mutation causing AD in their family. Once informed, most expressed a strong interest in genetic testing, largely motivated by the desire to be better prepared for the development of AD. Health professionals treating and investigators enrolling members from families with ADAD cannot assume that they fully understand the nature of the illness; therefore, providers should provide comprehensive information about ADAD and genetic testing.

Telephone Problem Solving for Service Members with Mild Traumatic Brain Injury: A Randomized, Clinical Trial.

Mild traumatic brain injury (mTBI) is a common injury for service members in recent military conflicts. There is insufficient evidence of how best to treat the consequences of mTBI. In a randomized, clinical trial, we evaluated the efficacy of telephone-delivered problem-solving treatment (PST) on psychological and physical symptoms in 356 post-deployment active duty service members from Joint Base Lewis McChord, Washington, and Fort Bragg, North Carolina. Members with medically confirmed mTBI sustained during deployment to Iraq and Afghanistan within the previous 24 months received PST or education-only (EO) interventions. The PST group received up to 12 biweekly telephone calls from a counselor for subject-selected problems. Both groups received 12 educational brochures describing common mTBI and post-deployment problems, with follow-up for all at 6 months (end of PST), and at 12 months. At 6 months, the PST group significantly improved on a measure of psychological distress (Brief Symptom Inventory; BSI-18) compared to the EO group (p = 0.005), but not on post-concussion symptoms (Rivermead Post-Concussion Symptoms Questionnaire [RPQ]; p = 0.19), the two primary endpoints. However, these effects did not persist at 12-month follow-up (BSI, p = 0.54; RPQ, p = 0.45). The PST group also had significant short-term improvement on secondary endpoints, including sleep (p = 0.01), depression (p = 0.03), post-traumatic stress disorder (p = 0.04), and physical functioning (p = 0.03). Participants preferred PST over EO (p < 0.001). Telephone-delivered PST appears to be a well-accepted treatment that offers promise for reducing psychological distress after combat-related mTBI and could be a useful adjunct treatment post-mTBI. Further studies are required to determine how to sustain its effects. (Trial registration: ClinicalTrials.gov Identifier: NCT01387490 https://clinicaltrials.gov ).

Results of the ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2).

BACKGROUND AND PURPOSE: Therapeutic hypothermia is a potent neuroprotectant approved for cerebral protection after neonatal hypoxia-ischemia and cardiac arrest. Therapeutic hypothermia for acute ischemic stroke is safe and feasible in pilot trials. We designed a study protocol to provide safer, faster therapeutic hypothermia in stroke patients. METHODS: Safety procedures and 4°C saline infusions for faster cooling were added to the ICTuS trial (Intravascular Cooling in the Treatment of Stroke) protocol. A femoral venous intravascular cooling catheter after intravenous recombinant tissue-type plasminogen activator in eligible patients provided 24 hours cooling followed by a 12-hour rewarm. Serial safety assessments and imaging were performed. The primary end point was 3-month modified Rankin score 0,1. RESULTS: Of the intended 1600 subjects, 120 were enrolled before the study was stopped. Randomly, 63 were to receive hypothermia plus antishivering treatment and 57 normothermia. Compared with previous studies, cooling rates were improved with a cold saline bolus, without fluid overload. The intention-to-treat primary outcome of 90-day modified Rankin Score 0,1 occurred in 33% hypothermia and 38% normothermia subjects, odds ratio (95% confidence interval) of 0.81 (0.36-1.85). Serious adverse events occurred equally. Mortality was 15.9% hypothermia and 8.8% normothermia subjects, odds ratio (95% confidence interval) of 1.95 (0.56-7.79). Pneumonia occurred in 19% hypothermia versus 10.5% in normothermia subjects, odds ratio (95% confidence interval) of 1.99 (0.63-6.98). CONCLUSIONS: Intravascular therapeutic hypothermia was confirmed to be safe and feasible in recombinant tissue-type plasminogen activator-treated acute ischemic stroke patients. Protocol changes designed to reduce pneumonia risk appeared to fail, although the sample is small. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01123161.

Accuracy of Stroke Diagnosis in Telestroke-Guided Tissue Plasminogen Activator Patients.

OBJECTIVES: The objective of the study is to assess the accuracy of final diagnosis in telestroke-guided tissue plasminogen activator (rt-PA) patients compared with bedside evaluation using computed tomography (CT) or magnetic resonance imaging (MRI) as a surrogate for final stroke diagnosis. The overall goal was to determine if telestroke had similar diagnostic accuracy as bedside evaluations in diagnosing rt-PA-treated patients. MATERIALS AND METHODS: We analyzed all acute stroke code calls who received intravenous rt-PA at our center from October 2013 to June 2015. Calls were grouped into patients who were initially evaluated by telestroke at a spoke partner site (spoke) and patients evaluated in person at the hub. Patients receiving additional neurointervention were excluded to avoid confounding. Relevant variables included severity of stroke (National Institutes of Health Stroke Scale [NIHSS]), rt-PA times, presence of intracranial hemorrhage (ICH), and primary outcome of CT or MRI evidence of stroke after rt-PA administration. Post-rt-PA imaging used included CT or MRI within 72 hours after treatment. RESULTS: Overall, 80 patients received intravenous rt-PA (spoke [n = 23] and hub [n = 57]). There was no difference in mean NIHSS score prior to treatment (10.3 ± 9.2 and 9.8 ± 8.4; P = .936), "onset-to-treatment" time (143.6 ± 53.5 minutes and 141.0 ± 54.1 minutes; P = .915), and ICH rate (13% and 8.8%; adjusted P = .898). The presence of radiographic evidence of stroke at spoke versus hub was not different (78.3% and 66.7%; adjusted P = .338). The most commonly used radiographic modality was MRI (MRI: 80%, CT: 20%). CONCLUSIONS: Using imaging as a surrogate for final diagnosis resulted in no difference in final stroke diagnosis rate between the groups, reinforcing that telestroke evaluations are as accurate as bedside evaluations in diagnosing acute stroke.

Visual Determination of Conjugate Eye Deviation on Computed Tomography Scan Predicts Diagnosis of Stroke Code Patients.

BACKGROUND: Head computed tomography (CT) is critical for stroke code evaluations and often happens prior to completion of the neurological exam. Eye deviation on neuroimaging (DeyeCOM sign) has utility for predicting stroke diagnosis and correlates with National Institutes of Health Stroke Scale (NIHSS) gaze score. We further assessed the utility of the DeyeCOM sign, without complex caliper-based eye deviation calculations, but simply with a visual determination method. METHODS: Patients with initial head CT and final diagnosis from an institutional review board-approved consecutive prospective registry of stroke codes at the University of California, San Diego, were included. Five stroke specialists and 1 neuroradiologist reviewed each CT. DeyeCOM+ patients were compared to DeyeCOM- patients (baseline characteristics, diagnosis, and NIHSS gaze score). Kappa statistics compared stroke specialists to neuroradiologist reads, and visual determination to caliper measurement of DeyeCOM sign. RESULTS: Of 181 patients, 46 were DeyeCOM+. Ischemic stroke was more commonly diagnosed in DeyeCOM+ patients compared to other diagnoses (P = .039). DeyeCOM+ patients were more likely to have an NIHSS gaze score of 1 or higher (P = .006). The NIHSS score of DeyeCOM+ stroke versus DeyeCOM- stroke patients was 8.3 ± 6.0 versus 6.7 ± 8.0 (P = .065). Functional outcomes were similar (P = .59). Stroke specialists had excellent agreement with the neuroradiologist (Κ = .89). Visual inspection had excellent agreement with the caliper method (Κ = .88). CONCLUSIONS: Using a time-sensitive visual determination of gaze deviation on imaging was predictive of ischemic stroke diagnosis and presence of NIHSS gaze score, and was consistent with the more complex caliper method. This study furthers the clinical utility of the DeyeCOM sign for predicting ischemic strokes.

Feasibility and Safety of Using External Counterpulsation to Augment Cerebral Blood Flow in Acute Ischemic Stroke-The Counterpulsation to Upgrade Forward Flow in Stroke (CUFFS) Trial.

BACKGROUND: External counterpulsation (ECP) increases perfusion to a variety of organs and may be helpful for acute stroke. METHODS: We conducted a single-blinded, prospective, randomized controlled feasibility and safety trial of ECP for acute middle cerebral artery (MCA) ischemic stroke. Twenty-three patients presenting within 48 hours of symptom onset were randomized into one of two groups. One group was treated with ECP for 1 hour at a pressure of up to 300 mmHg ("full pressure"). During the procedure, we also determined the highest possible pressure that would augment MCA mean flow velocity (MFV) by 15%. The other group was treated with ECP at 75 mmHg ("sham pressure"). Transcranial Doppler MCA flow velocities and National Institutes of Health Stroke Scale (NIHSS) scores of both groups were checked before, during, and after ECP. Outcomes were assessed at 30 days after randomization. RESULTS: Although the procedures were feasible to implement, there was a frequent inability to augment MFV by 15% despite maximal pressures in full-pressure patients. In sham-pressure patients, however, MFV frequently increased as shown by increases in peak systolic velocity and end diastolic velocity. In both groups, starting ECP was often associated with contemporaneous improvements in NIHSS stroke scores. There were no between-group differences in NIHSS, modified Rankin Scale Scores, and Barthel Indices, and no device or treatment-related serious adverse events, deaths, intracerebral hemorrhages, or episodes of acute neuro-worsening. CONCLUSIONS: ECP was safe and feasible to use in patients with acute ischemic stroke. It was associated with unexpected effects on flow velocity, and contemporaneous improvements in NIHSS score regardless of pressure used, with a possibility that even very low ECP pressures had an effect. Further study is warranted.

Accuracy of First Recorded "Last Known Normal" Times of Stroke Code Patients.

BACKGROUND: Given the time sensitivity of thrombolytic therapy, the accurate documentation of last known normal (LKN) time is crucial to ensure optimal management of stroke patients. This study investigates whether a difference exists between preliminary LKN times (first responders and emergency department practitioners) and revised LKN times (neurology/stroke practitioners), and what potential impact on emergent management of acute stroke this discrepancy may pose. METHODS: All stroke code patients from UC San Diego hospitals from October 2008 to July 2013 with treatment time data were included and grouped based on the disparity between preliminary LKN time and revised LKN time: preliminary earlier than revised, 2 times equal, and preliminary later than revised. We compared baseline characteristics, stroke code intervals, rates of recombinant tissue plasminogen activator (rt-PA) administration, 90-day modified Rankin Scale (mRS) score, discharge disposition, and symptomatic intracerebral hemorrhage. RESULTS: Of 261 patients, 73.6% had disparity between preliminary and revised times: 57.5% had later preliminary LKN than revised, and 16.1% had earlier preliminary LKN than revised. Baseline characteristics, stroke code speed, 90-day mRS score, rates of rt-PA administration, discharge disposition, or rates of symptomatic intracerebral hemorrhage were not significantly different between the groups. Among rt-PA-treated stroke patients whose preliminary time was earlier than the revised time, had the preliminary LKN been used, 29.4% would have had rt-PA withheld inappropriately. In those stroke patients excluded from rt-PA treatment for being outside the treatment window, whose preliminary time was later than the revised time, had the preliminary time been used, 69.7% would have been inappropriately treated outside the relevant rt-PA window. CONCLUSIONS: Most patients had disparity between preliminary and revised LKN times. Had the preliminary LKN time been used for acute stroke decision-making, 58% of patients would have potentially been treated outside the approved thrombolytic time window, with higher risk of adverse events, and 16% may have been inappropriately excluded from thrombolysis. This study highlights the need for training in the determination and refinement of the actual time of stroke onset, especially at hospitals without stroke expertise.

Comparing recruitment, retention, and safety reporting among geographic regions in multinational Alzheimer's disease clinical trials.

INTRODUCTION: Most Alzheimer's disease (AD) clinical trials enroll participants multinationally. Yet, few data exist to guide investigators and sponsors regarding the types of patients enrolled in these studies and whether participant characteristics vary by region. METHODS: We used data derived from four multinational phase III trials in mild to moderate AD to examine whether regional differences exist with regard to participant demographics, safety reporting, and baseline scores on the Mini Mental State Examination (MMSE), the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog11), the Clinical Dementia Rating scale Sum of Boxes (CDR-SB), the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), and the Neuropsychiatric Inventory (NPI). We assigned 31 participating nations to 7 geographic regions: North America, South America/Mexico, Western Europe/Israel, Eastern Europe/Russia, Australia/South Africa, Asia, and Japan. RESULTS: North America, Western Europe/Israel, and Australia/South Africa enrolled similar proportions of men, apolipoprotein E ε4 carriers, and participants with spouse study partners, whereas Asia, Eastern Europe/Russia, and South America/Mexico had lower proportions for these variables. North America and South America/Mexico enrolled older subjects, whereas Asia and South America/Mexico enrolled less-educated participants than the remaining regions. Approved AD therapy use differed among regions (range: 73% to 92%) and was highest in North America, Western Europe/Israel, and Japan. Dual therapy was most frequent in North America (48%). On the MMSE, North America, Western Europe/Israel, Japan, and Australia/South Africa had higher (better) scores, and Asia, South America/Mexico, and Eastern Europe/Russia had lower scores. Eastern Europe/Russia had more impaired ADAS-cog11 scores than all other regions. Eastern Europe/Russia and South America/Mexico had more impaired scores for the ADCS-ADL and the CDR-SB. Mean scores for the CDR-SB in Asia were milder than all regions except Japan. NPI scores were lower in Asia and Japan than in all other regions. Participants in North America and Western Europe/Israel reported more adverse events than those in Eastern Europe/Russia and Japan. CONCLUSIONS: These findings suggest that trial populations differ across geographic regions on most baseline characteristics and that multinational enrollment is associated with sample heterogeneity. The data provide initial guidance with regard to the regional differences that contribute to this heterogeneity and are important to consider when planning global trials.

Peripheral and central effects of γ-secretase inhibition by semagacestat in Alzheimer's disease.

INTRODUCTION: The negative efficacy study examining the γ-secretase inhibitor semagacestat in mild to moderate Alzheimer's disease (AD) included a number of biomarkers of the disease as well as safety outcomes. We analyzed these data to explore relationships between drug exposure and pharmacodynamic effects and to examine the correlations among outcome measures. METHODS: The study was a multicenter, randomized, placebo-controlled trial of two dose regimens of semagacestat and a placebo administered for 18 months to individuals with mild to moderate AD. Changes in measures of central and peripheral drug activity were compared between the three treatment groups using one-way analysis of variance. The relationship between changes in each of the outcome measures and measures of drug exposure and peripheral pharmacodynamic effect were assessed using Spearman's correlation coefficient. RESULTS: Assignment to the active treatment arms was associated with reduction in plasma amyloid-ß (Aß) peptides, increase in ventricular volume, decrease in cerebrospinal fluid phosphorylated tau (p-tau) and several other laboratory measures and adverse event categories. Within the active arms, exposure to drug, as indicated by area under the concentration curve (AUC) of blood concentration, was associated with reduction in plasma Aß peptides and a subset of laboratory changes and adverse event rates. Ventricular volume increase, right hippocampal volume loss and gastrointestinal symptoms were related to change in plasma Aß peptide but not AUC, supporting a link to inhibition of γ-secretase cleavage of the amyloid precursor protein. Cognitive decline correlated with ventricular expansion and reduction in p-tau. CONCLUSION: These findings may inform future studies of drugs targeting secretases involved in Aß generation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00594568. Registered 11 January 2008.

The "DeyeCOM Sign": Predictive Value in Acute Stroke Code Evaluations.

BACKGROUND: Rapid diagnosis in stroke is critical. Computed tomography is often performed initially, even before a neurologic examination. Gaze deviation has been correlated with stroke diagnosis in some cohorts. Conjugate gaze deviation on stroke code imaging, the "DeyeCOM sign," may have emergency stroke care implications. METHODS: We evaluated stroke code imaging from the University of California, San Diego database (2007-2013) for "DeyeCOM sign" diagnostic and predictive utility. Patients were grouped as DeyeCOM+ if conjugate gaze deviation was noted. The differences were assessed using the Fisher exact test for categorical and the Wilcoxon rank-sum test for continuous variables. RESULTS: We evaluated 342 patients; 106 (31%) were DeyeCOM+. Mean age was 63. The most common diagnoses in the DeyeCOM+ group were ischemic stroke (50.94%), transient ischemic attack (8.49%), other (8.49%), somatization (6.6%), and hemorrhage (5.66%). The National Institutes of Health Stroke Scale was greater in stroke patients than that in nonstroke (8.2 versus 3.8; P < .0001), and in DeyeCOM+ compared with DeyeCOM- (6.8 versus 5.6; P = .03). DeyeCOM+ patients were more likely to have a +gaze score (26.4% versus 9.8%; P < .0001), and +gaze patients were more likely to have final stroke diagnosis (26.0% versus 3.6%; P < .0001). There was no overall difference between groups in final stroke diagnosis; however, patients with deviation of 15° or more were more likely to have final diagnosis stroke (63.9% versus 47.9%; P = .03). CONCLUSIONS: DeyeCOM+ patients scored higher and were more likely to have +gaze on the stroke scale, and deviation of 15° or more was correlated with final diagnosis stroke. In current environments, there is pressure to complete stroke evaluations rapidly. Reliable imaging information obtained early (such as gaze deviation on scan correlating with scale score and final stroke diagnosis) could augment decision making even with negative imaging.

Defining mild stroke: outcomes analysis of treated and untreated mild stroke patients.

BACKGROUND: Mild deficit is a relative contraindication to administration of intravenous recombinant tissue plasminogen activator (IV rtPA) for acute ischemic stroke. However, what constitutes "mild" deficit is vague. Prior studies showed patients with mild strokes have substantial disability rates at hospital discharge and at 90 days. We investigated whether the application of a new definition altered the rates of disability overall and assessed the effects of thrombolysis. METHODS: This analysis included all adult acute ischemic stroke patients from a prospective registry of consecutive patients (University of California San Diego Specialized Programs of Translational Research in Acute Stroke (SPOTRIAS) database, 2003-2014) with 90-day modified Rankin Scale (mRS) score available who were defined as "mild" using either: National Institutes of Health Stroke Scale (NIHSS) 0-5 or a "Re-examining Acute Eligibility for Thrombolysis" (TREAT) Task Force definition (NIHSS 0-5 and nondisabling based on prespecified syndromes). Dichotomized 90-day mRS were compared between treated and untreated patients using the 2 definitions. RESULTS: Of 802 ischemic stroke patients with mRS scores available, 184 had baseline mRS (0) and met TREAT criteria; 45 (24.5%) were rtPA treated. Among the treated patients, 35.6% had 90-day mRS (2-6), versus 28.8% in the untreated group, a nonsignificant difference after adjusting for baseline NIHSS (P = .47). None of the 45 treated patients had symptomatic hemorrhage. Outcomes were similar using the simpler NIHSS 0-5 definition. CONCLUSIONS: About one third of mild stroke patients were not functionally independent at 90 days, irrespective of treatment or mild definition applied, calling into question the treatment efficacy of IV rtPA for mild strokes and what constitutes an appropriate definition of "mild." Randomized studies are necessary to determine rtPA treatment efficacy in mild stroke patients.

Association of Hispanic ethnicity with acute ischemic stroke care processes and outcomes.

BACKGROUND: Few studies have examined the actual hospital arrival mode, emergency department (ED) care processes, and early outcomes in Hispanic vs non-Hispanic acute ischemic stroke (AIS) patients. We evaluated processes and prognosis by Hispanic ethnicity among AIS patients encountered in urban setting. METHODS: We retrospectively reviewed prospectively-collected data on 1,117 AIS patients presenting within 12 hours of ictus to five hospitals in a tertiary-level stroke center network in San Diego, California. Variables of interest included pre-hospital factors, ED care processes, and favorable outcome (day-90 modified Rankin Scale [mRS] score of 0-1); all of which were adjusted for pre-specified covariates in a multivariable logistic regression model. RESULTS: There were 192 Hispanic AIS patients (17.2% of cohort) encountered from June 2004 to March 2011. Hispanic patients were significantly more likely to be younger, female, and diabetic. Hispanic patients arrived by ambulance (vs other arrival modes) less frequently (adjusted OR .56; 95% CI: .38-.81), trended toward a longer time of stroke onset to treatment decision (351.6 vs. 320.02 minutes, P=.07), and experienced a favorable day-90 outcome less often (adjusted OR .52, CI: .28-.96). However, for the day-90 outcome, there was no interaction between ambulance arrival and Hispanic ethnicity (P=.5614). DISCUSSION: Hispanic AIS patients in this study were less likely to arrive at the hospital by ambulance, and experienced half the odds of a favorable outcome compared to others. Strategies to boost ambulance utilization among Hispanic AIS patients and identify contributors to this worrisome outcome disparity are needed.