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.

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.

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.

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.

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.

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.

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.

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.

Imaging negative stroke: diagnoses and outcomes in intravenous tissue plasminogen activator-treated patients.

BACKGROUND: Intravenous (IV) Alteplase (tissue plasminogen activator [t-PA]) improves outcome in patients with acute ischemic stroke. Of those with full recovery, some may not have had ischemia. We analyzed the frequency and post-treatment outcomes of stroke code patients with no imaging evidence of stroke to establish the incidence of neuroimaging negative cerebral ischemia (NNCI) and stroke mimics treated with t-PA. In addition, we compared these patients with the group of stroke patients with imaging evidence of acute stroke to determine whether there was a difference in adverse events and functional outcomes. METHODS: We included all adult stroke patients treated with IV t-PA within 3 hours of stroke onset from the University of California, San Diego, Specialized Programs of Translational Research in Acute Stroke database through January 2013. The imaging positive stroke (IPS) code group comprised patients with neuroimaging evidence of acute ischemic stroke, whereas the imaging negative stroke code (INS) group included those patients without neuroimaging evidence of acute cerebral ischemia. All final diagnoses were reviewed by an adjudicating body. We reviewed medical records and neuroimaging; compared discharge diagnosis, 90-day modified Rankin Scale (mRS) score, and incidence of intracranial hemorrhage; and adjusted for age, admission National Institutes of Health Stroke Scale (NIHSS), prestroke mRS, and diabetes in multivariable models. RESULTS: We identified 106 patients, 74 IPS patients and 32 INS patients, who had similar baseline characteristics, except for baseline NIHSS (IPS 12.9 ± 8.2, INS 8.0 ± 5.6, P = .002) and incidence of cardiac arrhythmias (IPS 32.4%, INS 12.5%, P = .034). The diagnoses in the INS group were stroke (23, 72%)-representing NNCI, somatization (6, 19%), tumor (1, 3%), seizure (1, 3%), and migraine (1, 3%). All IPS patients were diagnosed with acute ischemic stroke. Adjusted for age, baseline NIHSS, prestroke mRS, and diabetes, the INS patients had significantly higher rates (odds ratio 3.04, P = .036) of good functional outcome (90-day mRS score 0-1). Intracerebral hemorrhage (ICH) was found in 24% of the IPS patients and was symptomatic in 6.8%. None of the INS patients had ICH. CONCLUSIONS: Because most INS patients were found to have NNCI, which may represent either transient ischemic attack or aborted stroke, and there were no intracerebral hemorrhages in the INS group, our data support the safety of administering IV t-PA to all patients in whom acute ischemic stroke is clinically suspected. We have demonstrated that NNCI patients and stroke mimics are common, and future larger scale prospective studies are required to delineate the true frequencies of each and to evaluate differences in outcomes.

Pooled assessment of computed tomography interpretation by vascular neurologists in the STRokE DOC telestroke network.

BACKGROUND AND PURPOSE: The objective of this pooled analysis was to determine the level of agreement between central read and each of 2 groups (spoke radiologists and hub vascular neurologists) in interpreting head computed tomography (CT) scans of stroke patients presenting to telestroke network hospitals. METHODS: The Stroke Team Remote Evaluation Using a Digital Observation Camera (STRokE DOC and STRokE DOC-AZ TIME) trials were prospective, randomized, and outcome blinded comparing telemedicine and teleradiology with telephone-only consultations. In each trial, the CT scans of the subjects were interpreted by the hub vascular neurologist in the telemedicine arm and by the spoke radiologist in the telephone arm. We obtained a central read for each CT using adjudicating committees blinded to treatment arm and outcome. The data were pooled and the results reported for the entire population. Kappa statistics and exact agreement rates were used to assess interobserver agreement for radiographic contraindication to recombinant tissue plasminogen activator (rt-PA), presence of hemorrhage, tumor, hyperdense artery, acute stroke, prior stroke, and early ischemic changes. RESULTS: Among 261 analyzed cases, the agreement with central read for the presence of radiological rt-PA contraindication was excellent for hub vascular neurologist (96.2%, κ = .81, 95% CI .64-.97), spoke radiologist report (94.7%, κ = .64, 95% CI .39-.88), and overall (95.4%, κ = .74, 95% CI .59-.88). For rt-PA-treated patients (N = 65), overall agreement was 98.5%, and vascular neurologist agreement with central read was 100%. CONCLUSIONS: Both vascular neurologists and reports from spoke radiologists had excellent reliability in identifying radiologic rt-PA contraindications. These pooled findings demonstrate that telestroke evaluation of head CT scans for acute rt-PA assessments is reliable.

Does symptom onset to primary stroke center time goals affect stroke outcome?

BACKGROUND: Treating acute ischemic stroke (AIS) within 4.5 hours and door-to-needle time of less than 60 minutes may optimize recovery. It is unknown if onset to Primary Stroke Center (PSC) time goals affect outcome. The purpose of this study was to examine effects of symptom onset to PSC time goals on outcome. METHODS: Analysis included prospectively collected data from the University of California San Diego Specialized Program of Treatment Research in Acute Stroke. All AIS patients treated with intravenous recombinant tissue plasminogen activator were included if treated within 270 minutes, and 90-day modified Rankin Scale (mRS) score was known. Primary outcome of the 90-day mRS was analyzed using multivariable logistic regression. Good outcome was defined as a 90-day mRS score of 0-2. Variables assessed were time from onset to arrival, stroke code, neurologic exam, imaging, laboratories, treatment decision, and treatment (by quartiles). RESULTS: Two hundred ninety-one patients were included (49.8% female, mean age 70.6 ± 16.1, median National Institutes of Health Stroke Scale 10, SD = 8.5). Good outcome occurred in 45% of patients. Significant baseline differences included HTN (P ≤ .001), A fib (P ≤ .001), prestroke mRS (P < .001), and Hispanic ethnicity (P = .011). Comparing good with poor outcome groups: mean onset to arrival was 70.6 min versus 62.5 min (P = .129) and mean onset to treatment was 140.1 min versus 134.9 min (P = .118). Controlling for prespecified covariates, no PSC time goals were significant predictors of the 90-day outcome. CONCLUSIONS: In our Comprehensive Stroke Center (CSC), onset to PSC time goals were not significant predictors of the 90-day outcome. Expedited care processes in CSC may compensate for differences in outcome. These results should be validated in a larger cohort and in PSCs versus CSCs.

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.

Trends in antihypertensive drug prescription patterns among ambulatory stroke patients in the United States, 2000-2009.

BACKGROUND: Although the ambulatory setting is recognized as the best arena for optimizing antihypertensive drug treatment after a stroke, little is known about recent office-based antihypertensive drug treatment patterns in the United States. We assessed national trends in antihypertensive treatment for stroke patients in office-based medical practice. METHODS: Data from the 2000-2009 National Ambulatory Medical Care Surveys were analyzed comprising outpatient visits to physicians in office-based practice by patients aged 40 years or older with a diagnosis of stroke (weighted estimate=46,317,269). The main outcome measure was visits with a prescription of antihypertensive medication(s). RESULTS: The proportion of total visits that included a prescription of antihypertensive medication was 35.6% in 2000-2002, 29.5% in 2003-2005, and 49.3% in 2006-2009 (P=.002); 50.9% were primary care physician (PCP) visits versus 26.2% neurologist visits (P<.0001). Age-adjusted logistic regression analyses confirmed a higher prescription rate in 2006-2009 versus 2000-2002 (1.81; 95% confidence interval [CI], 1.10-2.96) and PCP versus neurologists (2.82; 95% CI, 1.86-4.27). Use of 2 or more agent classes was 31.6% in 2000-2002, 44.2% in 2003-2005, and 56.7% in 2006-2009 (P=.014). Age-adjusted logistic regression analyses confirmed a higher prescription rate of 2 or more agent classes in 2006-2009 versus 2000-2002 (2.96; 95% CI, 1.40-6.24). There were no significant differences in agent class type or number between neurologists versus PCPs. CONCLUSIONS: Over the last decade, there was a significant rise in the use of antihypertensive drugs and combination of agent classes for patients aged 40 years or older seen in an ambulatory setting with a diagnosis of stroke. PCPs were more likely than neurologists to prescribe these agents.

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.

CT interpretation in a telestroke network: agreement among a spoke radiologist, hub vascular neurologist, and hub neuroradiologist.

BACKGROUND AND PURPOSE: The American Stroke Association guidelines emphasized the need for further high-quality studies that assess agreement by radiologists and nonradiologists engaged in emergency telestroke assessments and decision-making. Therefore, the objective of this study was to determine the level of agreement of baseline brain CT scan interpretations of patients with acute stroke presenting to telestroke spoke hospitals between central reading committee neuroradiologists and each of 2 groups, spoke hospital radiologists and hub hospital vascular neurologists (telestrokologists). METHODS: The Stroke Team Remote Evaluation Using a Digital Observation Camera Arizona trial was a prospective, urban single-hub, rural 2-spoke, randomized, blinded, controlled trial of a 2-way, site-independent, audiovisual telemedicine and teleradiology system designed for remote evaluation of adult patients with acute stroke versus telephone consultation to assess eligibility for treatment with intravenous thrombolysis. In the telemedicine arm, the subjects' CT scans were interpreted by the hub telestrokologist and in the telephone arm by the spoke radiologist. All subjects' CT scans were subsequently interpreted centrally, independently, and blindly by 2 hub neuroradiologists. The primary CT outcome was determination of a CT-based contraindication to thrombolytic treatment. Kappa statistics and exact agreement rates were used to analyze interobserver agreement. RESULTS: Fifty-four subjects underwent random assignment. The overall agreement for the presence of radiological contraindications to thrombolysis was excellent (0.91) and did not differ substantially between the hub telestrokologist to neuroradiologist and spoke radiologist to neuroradiologist (0.92 and 0.89, respectively). CONCLUSIONS: In the context of a telestroke network designed to assess patients with acute stroke syndromes, agreement over the presence or absence of radiological contraindications to thrombolysis was excellent whether the comparisons were between a telestrokologist and neuroradiologist or between spoke radiologist and neuroradiologist. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00623350.

Comprehensive stroke centers and the 'weekend effect': the SPOTRIAS experience.

BACKGROUND AND PURPOSE: Previous studies have found mortality among ischemic stroke patients to be higher on weekends. We sought to evaluate whether weekend admission was associated with worse outcomes in a large comprehensive stroke center (CSC) cohort. METHODS: Consecutive ischemic stroke patients presenting within 6 h of symptom onset were identified using the 8 CSC SPOTRIAS (Specialized Programs of Translational Research in Acute Stroke) database. Patients who received intra-arterial therapy or who were enrolled in a nonobservational clinical trial were excluded. All patients meeting the inclusion criteria were then divided into two groups: weekday admissions or weekend admissions. Weekend admission was defined as Friday 17:01 to Monday 08:59. The remainder were classified as weekday admissions. Multivariate logistic regression was used, adjusting for age, stroke severity on admission [according to the National Institutes of Health Stroke Scale (NIHSS)] and admission glucose, in order to compare the outcomes of the weekend versus the weekday groups. RESULTS: Eight thousand five hundred and eighty-one subjects from the combined SPOTRIAS database were screened from 2002 to 2009; 2,090 (24.4%) of these met the inclusion criteria. There was no significant difference in tissue plasminogen activator treatment rates between the weekday and weekend groups (58.5 vs. 60.4%, p = 0.397). Weekend admission was not a significant independent predictor of inhospital mortality (8.4 vs. 9.9%, p = 0.056), length of stay (4 vs. 5 days, p = 0.442), favorable discharge disposition (38.0 vs. 42.2%, p = 0.122), favorable functional outcome at discharge (41.6 vs. 43.4%, p = 0.805), favorable 90-day functional outcome (54.2 vs. 46.9%, p = 0.301), or 90-day mortality (18.2 vs. 19.8%, p = 0.680) when adjusting for age, NIHSS and admission glucose. CONCLUSIONS: In this large cohort of ischemic stroke patients treated at CSCs, we did not observe the 'weekend effect.' This may be due to access to stroke specialists 24 h a day on 365 days a year, nurses with stroke experience and the organized system for delivering care that is available at CSCs. These results suggest that EMS protocol should be reexamined regarding the preferential delivery of weekend stroke victims to hospitals that provide all levels of reperfusion therapy. This further highlights the importance of organized stroke care.

Determinants of effective cooling during endovascular hypothermia.

BACKGROUND: Therapeutic hypothermia is a promising neuroprotective therapy with multiple mechanisms of action. We demonstrated the feasibility of thrombolysis combined with endovascular hypothermia, but not all patients achieved effective cooling. We sought to identify the factors that determined effective cooling. METHODS: In 26 patients who underwent endovascular hypothermia, we computed four measures of effective cooling: time to reach target; Area-Under-the-Curve (AUC) 34 ratio; AUC-34; and AUC-35. By multivariate regression, we examined the effects of age, weight, starting temperature, body mass index, body surface area (BSA), gender, shivering, and total meperidine dose on the four outcome measures. RESULTS: In univariate analyses, all four outcome measures were significantly influenced by BSA (p < 0.01 in all univariate analyses). Time to reach target temperature was quicker in older patients (p < 0.01). Shivering and meperidine dose were highly intercorrelated (r = 0.6, p < 0.01) and both marginally influenced all four outcome measures. In multivariate analysis, AUC ratio and time to reach target temperature were significantly influenced by BSA (p < 0.01) and meperidine (p < 0.05); AUC-34 was influenced only by BSA (p < 0.01). The AUC-35 was influenced by BSA (p < 0.01), shivering, and total meperidine dose (p < 0.05). CONCLUSIONS: The most important determinant of effective cooling during endovascular hypothermia is BSA; larger patients are more difficult to cool and maintain in therapeutic range. Older patients cool more quickly. Shivering was well controlled by the combination of meperidine, buspirone, and surface counter-warming and only minimally influenced cooling effectiveness. Future trials of therapeutic hypothermia may include added measures to cool larger patients more effectively.

Efficacy of telemedicine for stroke: pooled analysis of the Stroke Team Remote Evaluation Using a Digital Observation Camera (STRokE DOC) and STRokE DOC Arizona telestroke trials.

BACKGROUND AND PURPOSE: Telemedicine can disseminate vascular neurology expertise and optimize recombinant tissue plasminogen activator (rt-PA) use for acute ischemic stroke in rural underserved communities. The purpose of this study was to prospectively assess whether telemedicine or telephone was superior for decision-making. METHODS: The study design is a pooled analysis of two identically designed randomized controlled trials conducted in a multistate hub and spoke telestroke network setting with acute stroke syndrome patients, comparing telemedicine versus telephone-only consultations. From each trial, common data elements were pooled to assess, principally, for correctness of thrombolysis decision-making. Secondary outcomes included rt-PA use rate, 90-day functional outcome, post-thrombolysis intracranial hemorrhage, and data completeness. RESULTS: Two hundred seventy-six pooled patients were evaluated. Correct thrombolysis eligibility decisions were made more often with telemedicine (96% telemedicine, 83% telephone; odds ratio [OR] 4.2; 95% confidence interval [CI] 1.69-10.46; p=0.002). Intravenous rt-PA usage was 26% (29% telemedicine, 24% telephone; OR 1.27; 95% CI 0.71-2.25; p=0.41). Ninety-day outcomes were not different for Barthel Index, modified Rankin Scale, or mortality. There was no difference in post-thrombolysis intracranial hemorrhage (8% telemedicine, 6% telephone; p>0.999). CONCLUSIONS: This pooled analysis supports the hypothesis that stroke telemedicine consultations, compared with telephone-only, result in more accurate decision-making. Together with high rt-PA utilization rate, low post-rt-PA intracranial hemorrhage rate, and acceptable patient outcome, the results confirm that telemedicine is a viable consultative tool for acute stroke. The replication of the hub and spoke network infrastructure supports the generalizability of telemedicine when used in broader settings.