Citations

AbstractBackgroundThe U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a two‐year randomized controlled trial designed to evaluate the effects of lifestyle interventions on older adults aged 60‐79 years. The POINTER Imaging ancillary study employs arterial spin labeling (ASL) magnetic resonance imaging (MRI) with two inversion times, enabling the mapping of arterial transit time (ATT) and the investigation of its relationship with dementia risk factors. This study examines the effect of the Framingham Risk Score (FRS) on ATT, which provides hemodynamic information on the cerebral vasculature.MethodA subset of POINTER Imaging participants (n = 134; F/M = 81/53; age = 68.1±5.1; FRS = 11.3±10.4) from two imaging sites underwent two ASL MRI scans during the baseline session. Two 3D Pulsed ASL scans were obtained with TI1 of 790ms and TI2 values of 2000ms or 2750ms, providing delay times (between labeling and imaging) of 1210ms or 1960ms. ATT, the time required for blood to travel from the neck to the tissue, was estimated in the range of 1210ms and 1960ms using a kinetic model (Figure 1). ATT maps were normalized to a standard space, and a voxel‐wise linear regression (ATT∼age+sex+log(FRS)) was performed on ATT maps in gray matter to assess the effect of FRS on ATT. To control false positives, clusters smaller than 1.4ml were removed based on a simulation with α = 0.05.ResultFigure 2 depicts three clusters found in the occipital, precuneus and frontal gray matter regions, all of which demonstrate a positive relationship between ATT and log(FRS). Participants with higher FRS exhibit prolonged mean ATT values in the clusters as shown in Figure 3. After stratifying into sex groups, both groups show the same direction.ConclusionAlthough the detectable range of ATT with two ASL scans was limited, the analysis suggests that an increased risk of cardiovascular disease, as quantified by the Framingham Risk Score, can serve as an indicator of potential cerebrovascular disease leading to prolonged ATT, which is associated with arterial stiffness, and vascular resistance. The clusters demonstrating the association between FRS and ATT are the brain regions that may have heightened vulnerability to vascular risk factors, according to previous studies.

AbstractBackgroundEthnoculturally diverse individuals from underrepresented populations (URPs), including but not limited to Black/African American and Hispanic/Latinx adults, are disproportionally affected by Alzheimer’s disease (AD) compared to non‐Hispanic/Latinx white (NLW) adults. However, URPs have historically been under‐included in AD studies. The objective of this study is to describe efforts, and the results of those efforts, to increase enrollment and engagement of ethnoculturally diverse individuals from URPs in the Alzheimer’s Disease Neuroimaging Initiative 3 (ADNI3).MethodsEfforts undertaken by ADNI to increase enrollment and engagement of URPs included (1) launching of a Diversity Taskforce (DVTF) lead by two health disparities experts in July 2020, charged with overseeing ADNI’s mission in this space. Specific DVTF activities included: (2) the establishment, funding, and instrumental support (e.g., training, consultation, resources) of diversity at 13 ADNI3 sites; (3) changing ADNI protocol to facilitate research participation of URPs (e.g., optional lumbar puncture and sharing of amyloid PET results); (4) hiring a marketing agency to launch culturally‐informed digital/social media campaigns for the 13 DVTF Sites, with local websites; (5) development of a database to capture performance metrics of inclusion efforts at the 13 DVTF Sites; and (6) formation of a six‐member External Advisory Board, comprised of leaders in health disparities research, to guide DVTF efforts.ResultURP enrollment at these 13 DVTF sites improved from 1.1 URPs per month previously to >4 URPs per month, a 264% increase. Across all 59 ADNI sites, overall enrollment of ethnoculturally diverse individuals from URPs went from 89 (16.8%) to 126 (21.1%), representing a 25% increase in enrollment between May 2020 and September 2021. Moreover, since February 1st, 2021, ADNI enrolled 43 new participants of which 33 (77%) were from URPs.ConclusionIt is possible to improve the enrollment and retention of URPs in AD research using a multi‐pronged community engaged approach that also provides human capital, infrastructure, and financial resources. The success of the DVTF has led to the formation of a new Engagement Core in ADNI4, tasked with implementing a scaled‐up culturally‐informed, community‐engaged research approach to URP inclusion and retention across all 59 ADNI sites.

AbstractBackgroundThe Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a longitudinal observational study of individuals across the dementia spectrum that validates biomarkers for clinical trials. The newest phase of the study, ADNI4, aims to substantially increase the inclusion of underrepresented populations to improve generalizability of ADNI results. Novel biomarkers, including a speech‐based cognitive assessment and blood‐based plasma biomarkers, are integrated into the study design as key participant screening measures.MethodTo help achieve recruitment goals, ADNI4 uses a new, multi‐phase approach to remotely enroll and screen participants. A large study cohort (aiming for 20,000+ participants) provide initial screening data via an online study platform including demographics, medical history related to study exclusionary criteria, and results from a speech‐based cognitive memory assessment (Novoic Ltd. Storyteller test) and a measure of subjective cognitive/functional decline (Everyday Cognition (ECog) 12‐item). Based on screening results, a subset of online study participants is referred to a Quest Diagnostics location to provide a blood sample for plasma biomarker analysis (aiming for 4,000+ participants). Finally, select participants are referred to ADNI clinical sites for in‐depth characterization (goal of up to 1,500 in‐clinic participants).ResultWe report ADNI’s initial approach for selecting participants from the online screening cohort to undergo plasma biomarker phenotyping, and subsequent selection to a clinical site. Participants from diverse demographic backgrounds (especially for race, ethnicity, and/or education) and those with a higher estimated likelihood of cognitive impairment are given priority in the referral selection process. Likelihood of cognitive impairment is assessed using results from subjective memory complaint questions, responses to the ECog 12‐item questionnaire, and the Novoic Storyteller results. Individuals with results showing high concordance across these measures are prioritized, as well as those who have subsequent plasma results indicating biomarker positivity.ConclusionWeighing the various study requirements and inclusivity goals increases the complexity of participant selection decision making, and is a time‐intensive process. As the ADNI study progresses we aim to automate the participant selection/referral process by developing algorithms that account and encode for changing study prioritizations and dynamics across numerous dimensions. Learnings from ADNI4’s new remote processes will help inform future clinical trial design.

AbstractBackgroundSmartphone‐based cognitive and motor tests enable frequent remote assessments in observational research studies and clinical trials, limiting travel burden and increasing access to research for underrepresented groups. One such smartphone tool is the ALLFTD Mobile App, which was designed to capture the clinical features of neurodegenerative diseases via a battery of cognitive, speech, and motor tasks. In this study, we focus on recruiting a demographically diverse normative sample. We have partnered with the UCSF Brain Health Registry (BHR) to recruit 1,000 cognitively healthy participants across the lifespan. Here we describe the study design and initial feasibility results.MethodsWe designed an automated workflow in which participants never interact with the study team except for troubleshooting. BHR participants without reported cognitive impairment were contacted by email to participate in this study (n = 668). Interested participants downloaded the app onto their smartphone and completed in‐app electronic consent. They were asked to complete three ∼30‐minute sessions of cognitive, motor and speech measures over two weeks. Adherence was determined by evaluating the completion rate of app tasks. In a subset who completed a user experience questionnaire (n = 116), responses were quantified using descriptive statistics.ResultsThe current enrollment rate is 23.20% (155/668) of contacted participants. Average age is 62 (SD = 8.2, range = 25‐84). Average adherence is 76%. Participants reported a range of perceived task difficulty: 38% indicated tasks were “very easy” or “somewhat easy”, 26% indicated they were “neutral,” 36% found the tasks “somewhat difficult,” and none reported them to be “very difficult.” The time commitment was reported to be acceptable by 97% of participants, and 20% were willing to complete additional tasks. Over half (59%) of participants indicated that they preferred using a smartphone to complete cognitive assessments over traditional pen‐and‐paper measures.ConclusionsOur preliminary results demonstrate the feasibility and acceptability of recruiting participants, including older adults, through a registry and conducting remote smartphone testing via a fully automated workflow that is highly scalable. Future analysis will study the effects of demographic factors on feasibility and investigate the reliability and validity of the app measures in this sample.

AbstractBackgroundAdults with Down Syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia as they age. This is attributed to triplication of the amyloid precursor protein gene. Recent work demonstrated that amyloid is elevated in DS and accumulates in a similar topography to autosomal dominant AD (ADAD). Tau accumulation is the second hallmark of AD and may be measured using tau positron emission tomography (PET) imaging. The pattern of tau accumulation remains unknown in DS.MethodIn a cross‐sectional analysis we evaluated amyloid and tau positron emission tomography (PET) in 124 participants with DS (109 cognitively stable, 8 symptomatic, 7 no consensus), 29 ADAD mutation carriers (26 asymptomatic, 3 symptomatic), and 201 cognitively normal non‐mutation carriers (CN). Regional cortical standard uptake value ratios (SUVR) for tau imaging were obtained and compared by cognitive status. Similarly, regional cortical amyloid SUVR were obtained and converted to centiloids. We then compared the magnitude of tau burden as well as spatial spread of tau across groups relative to amyloid burden.ResultCompared to CN, tau PET binding was elevated in participants with (µDS = 2.12 ± 0.22 SUVR, µADAD = 2.52 ± 0.37 SUVR) and without (µDS = 1.24 ± 0.15 SUVR, µADAD = 1.16 ± 0.19 SUVR) cognitive changes. For both groups, tau increased with increasing amyloid (centiloids). In some regions, DS had greater tau burden for a given amyloid level (centiloids) (Figure 1). There was increased spatial distribution of tau throughout the brain for participants with DS compared to CN. In contrast, tau burden was more focal in participants with ADAD with tau primarily elevated in posterior regions (Figure 2).ConclusionWhile tau burden was higher with symptomatic disease for both groups, significant differences existed in the overall amount and spatial spread. Tau spread was greatest in participants with DS and more diffuse compared to ADAD. These results indicate a substantial tau burden is present in DS, and suggest not only anti‐amyloid but also tau‐reducing agents should be considered for treating cognitive decline in adults with DS.

Introduction: The ICD Sports Registry demonstrated that many athletes with ICDs can participate in competitive sports without death, failure to defibrillate, or physical injury. However, sudden cardiac arrest is more prevalent and has worse outcomes in Black compared to White individuals in the general population and among athletes. Outcomes of sports participation for Black athletes with ICDs have not been described. Aim: To describe the risk of arrhythmia and efficacy of ICDs in Black athletes. Methods: This is a post-hoc subgroup analysis of the ICD Sports Registry, which enrolled athletes with ICDs age 10 to 60, participating in organized, competitive sports, and followed them prospectively for four years. The endpoints and methods are reported previously. Results: Among the 440 athletes, 15 were Black and 410 white. Among the Black athletes, hypertrophic cardiomyopathy was the most common diagnosis (40%) and 87% were implanted for secondary prevention or syncope (vs 69% in White athletes). Most common sports were basketball (8), softball (4), and running (3), with 7 Black athletes competing on varsity/junior varsity/traveling teams. Among the Black athletes, there were no appropriate shocks during sports, among white athletes, 7% received an appropriate shock during sports. Among Black athletes, there was one appropriate shock event for ventricular tachycardia (7%), a VT storm in an athlete with idiopathic VF, non-sports-related. Among white athletes, 10% received appropriate shocks during non-sports activities. Two Black athletes (13%) received an inappropriate shock, one competition-related (sinus tachycardia) and the other for T wave oversensing at rest, vs 12% of white athletes. There were no sports-related deaths, arrests, or arrhythmia-related injuries in either group. Conclusions: Black athletes represented a small subset of the ICD Sports Registry. Reasons for this are unknown, but may include disparities in ICD implantation and/or in research recruitment/ participation. These Black athletes experienced both appropriate and inappropriate shocks as did white athletes. These data do not suggest a signal for harm for competitive sports participation for Black athletes with ICDs but larger studies are needed.

Introduction: Exposure to high altitude results in hypobaric hypoxia, leading to physiological changes in the cardiovascular system that may result in dyspnea. Hypoxic simulation testing (HSTs) simulates changes in physiology that occur at a specific altitude. Hypothesis: The use of transthoracic echocardiography (TTE) during HST can detect the raise in right-sided pressures revealing underlying causes of high-altitude dyspnea. Methods: We performed a prospective observational study of consecutive patients with unexplained dyspnea at high altitude who were referred to an aerospace medicine program at a single institution between August 2021 and March 2023. Reduced FiO 2 was administered for 20 minutes to simulate altitude levels specific to patients’ history. TTE images were obtained at baseline and during peak hypoxia to evaluate right ventricular (RV) function, RV systolic pressure, and any possible shunts. Result: The study included 27 patients, with a mean age of 64.7 ±14.4 years and 14 (51.9%) females. No significant abnormalities were seen on baseline TTE and no significant differences in blood pressure and heart rate between baseline and hypoxia simulation were detected. Notably, RV systolic pressure increased at peak hypoxia, while RV systolic function declined as shown by a decrease in S’ wave and TAPSE ( Figure 1 ). Additionally, right to left shunts were present in 19 (70.4%) patients. Of these, four patients (21.1%) had shunts present at baseline with no changes at peak hypoxia, while the severity of shunts increased at peak hypoxia in eight cases (42.1%) and the shunts were only evident during hypoxia in seven patients (36.8%). Conclusion: TTE during HST provides valuable information by revealing the presence of symptomatic, sustained shunts and confirming the decline in RV hemodynamics explaining dyspnea at altitude. Further studies are necessary to establish the optimal clinical role of this physiologic method.

Abstract Purpose: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. Patients and Methods: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy “graduates” if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. Results: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%–99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. Conclusions: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.

Abstract Background and Aims Racial and ethnic disparities exist in the treatment of IBD. These disparities exist in adult vaccine uptake among the general population and may extend to patients with IBD. The primary aim of this study was to determine whether racial, ethnic, or geographic disparities existed in influenza vaccine uptake among patients with IBD. Methods We performed a multicenter, retrospective cohort study evaluating adult vaccine uptake among patients with IBD seen at two tertiary referral centers between September 2019 and February 2020. The primary outcome was to determine if racial/ethnic and geographic disparities existed in influenza vaccine uptake for the two prior seasons. Our secondary outcomes were to determine if disparities existed for pneumococcal, zoster, or hepatitis B vaccines. Results Among the 2453 patients who met the inclusion criteria, most identified as non-Hispanic White (89.9%), were on immunosuppressive therapy (74.5%), and received the influenza vaccine in both seasons (56.0%). Older age (prevalence ratio (PR) 0.98; 95% confidence interval (95%CI) 0.98-0.99; P < .001) and non-Hispanic White patients (PR 0.76, 95%CI 0.59–0.98, P < 0.03) were significantly more likely to be immunized. Black patients (PR 1.37; 95%CI 1.18–1.59; P < .001) and those living in underserved geographic areas (PR 1.35; 95%CI 1.17–1.56; P < 0.001) were less likely to be immunized. Racial/ethnic and geographic disparities were identified for pneumococcal, zoster, and hepatitis B vaccine uptake. Conclusions Racial and ethnic vaccination uptake disparities exist among patients with IBD; patients from medically underserved areas are also vulnerable to these disparities Studies identifying patient, provider, and system-level opportunities to address these disparities are needed.