Ethical, legal, and policy challenges in field-based neuroimaging research using emerging portable MRI technologies: guidance for investigators and for oversight.

Researchers are rapidly developing and deploying highly portable MRI technology to conduct field-based research. The new technology will widen access to include new investigators in remote and unconventional settings and will facilitate greater inclusion of rural, economically disadvantaged, and historically underrepresented populations. To address the ethical, legal, and societal issues raised by highly accessible and portable MRI, an interdisciplinary Working Group (WG) engaged in a multi-year structured process of analysis and consensus building, informed by empirical research on the perspectives of experts and the general public. This article presents the WG's consensus recommendations. These recommendations address technology quality control, design and oversight of research, including safety of research participants and others in the scanning environment, engagement of diverse participants, therapeutic misconception, use of artificial intelligence algorithms to acquire and analyze MRI data, data privacy and security, return of results and managing incidental findings, and research participant data access and control.

Diversifying the research landscape: Assessing barriers to research for underrepresented populations in an online study of Parkinson's disease.

Despite federal regulations mandating the inclusion of underrepresented groups in research, recruiting diverse participants remains challenging. Identifying and implementing solutions to recruitment barriers in real time might increase the participation of underrepresented groups. Hence, the present study created a comprehensive dashboard of barriers to research participation. Barriers to participation were recorded in real time for prospective participants. Overall, 230 prospective participants expressed interest in the study but were unable to join due to one or more barriers. Awareness of the most common obstacles to research in real time will give researchers valuable data to meaningfully modify recruitment methods.

Preparing for pragmatic trials in dementia care: Health equity considerations for nonpharmacological interventions.

Inequities with regard to brain health, economic costs, and the evidence base for dementia care continue. Achieving health equity in dementia care requires rigorous efforts that ensure disproportionately affected populations participate fully in-and benefit from-clinical research. Embedding-proven interventions under real-world conditions and within existing healthcare systems have the potential to examine the effectiveness of an intervention, improve dementia care, and leverage the use of existing resources. Developing embedded pragmatic controlled trials (ePCT) research designs for nonpharmacological dementia care interventions involves a plethora of a priori assumptions and decisions. Although frameworks exist to determine whether interventions are "ready" for ePCT, there is no heuristic to assess health equity-readiness. We discuss health equity considerations, case examples, and research strategies across ePCT study domains of evidence, risk, and alignment. Future discussions regarding health equity considerations across other domains are needed.

Designing the Fostering Inclusivity in Research Engagement for Underrepresented Populations in Parkinson's Disease study.

BACKGROUND: Population reflective research enrollment improves study generalizability and disease knowledge. Nevertheless, the proportion of underrepresented groups (URGs) in Parkinson's disease (PD) research remains low. Hence, the current manuscript describes the process of designing a study to analyze the effectiveness of strategies to overcome barriers to URG recruitment in PD research. METHODS: The Fostering Inclusivity in Research Engagement for Underrepresented Populations in Parkinson's Disease (FIRE-UP PD) study asked participating sites to identify a URG or geographical region to target to assess knowledge and attitudes toward PD research as well as increase Fox Insight (an online study with The Michael J. Fox Foundation) participation across eight months. URGs were defined as racial and ethnic minorities, women, rural populations, and low socioeconomic status groups. Participating sites were paired based on their proposed interventions and were randomly assigned to either the intervention or control condition. RESULTS: The FIRE-UP PD study was divided into pre-intervention, intervention, and post-intervention periods to measure changes in awareness and trust in PD research along with engagement and interest in PD protocols through the use of several surveys. Interventions included developing educational tools to engage local communities, building partnerships within local PD communities, and recruiting stakeholders to reimagine medical and research information for the community. CONCLUSION: Improving representation in research is a crucial step toward improving access to PD diagnoses and treatments. This is one of the first multi-site PD research studies to include community engagement to address barriers to research participation and improve research recruitment of URGs.

Traversing the Aging Research and Health Equity Divide: Toward Intersectional Frameworks of Research Justice and Participation.

Meaningful reductions in racial and ethnic inequities in chronic diseases of aging remain unlikely without major advancements in the inclusion of minoritized populations in aging research. While sparse, studies investigating research participation disparities have predominantly focused on individual-level factors and behavioral change, overlooking the influence of study design, structural factors, and social determinants of health on participation. This is also reflected in conventional practices that consistently fail to address established participation barriers, such as study requirements that impose financial, transportation, linguistic, and/or logistical barriers that disproportionately burden participants belonging to minoritized populations. These shortcomings not only risk exacerbating distrust toward research and researchers, but also introduce significant selection biases, diminishing our ability to detect differential mechanisms of risk, resilience, and response to interventions across subpopulations. This forum article examines the intersecting factors that drive both health inequities in aging and disparate participation in aging research among minoritized populations. Using an intersectional, social justice, and emancipatory lens, we characterize the role of social determinants, historical contexts, and contemporaneous structures in shaping research accessibility and inclusion. We also introduce frameworks to accelerate transformative theoretical approaches to fostering equitable inclusion of minoritized populations in aging research.

Care and Precision Medicine Research in the Time of COVID-19.

Purpose: Enhancing the bidirectional benefit of precision medicine research infrastructure may advance equity in research participation for diverse groups. This study explores the use of research infrastructure to provide human-centered COVID-19 resources to participants as a part of their research participation. Design: The All of Us New England (AoUNE) consortium research team developed standardized check-in telephone calls to ask participants about their well-being and share COVID-19 resources. Participants: A total of 20,559 participants in the AoUNE consortium received a COVID-19 check-in call. Methods: Research assistants called participants during March-April 2020, distributed COVID-19 resources to interested participants, and subsequently rated call tone. Results: Of the total cohort participants called, 8,512 (41%) spoke with a research team member. The majority of calls were rated as positive or neutral; only 3% rated as negative. African American and Black as well as Hispanic populations requested COVID-19 resources at higher rates than other groups. Conclusions: Calls made to AoUNE participants were received positively by diverse groups. These findings may have implications for participant-centered engagement strategies in precision medicine research.

The Urgency of Justice in Research: Beyond COVID-19.

The striking imbalance between disease incidence and mortality among minorities across health conditions, including coronavirus disease 2019 (COVID-19) highlights their under-inclusion in research. Here, we propose actions that can be adopted by the biomedical scientific community to address long-standing ethical and scientific barriers to equitable representation of diverse populations in research.

Achieving Health Equity in Embedded Pragmatic Trials for People Living with Dementia and Their Family Caregivers.

Embedded pragmatic clinical trials (ePCTs) advance research on Alzheimer's disease/Alzheimer's disease and related dementias (AD/ADRD) in real-world contexts; however, health equity issues have not yet been fully considered, assessed, or integrated into ePCT designs. Health disparity populations may not be well represented in ePCTs without special efforts to identify and successfully recruit sites of care that serve larger numbers of these populations. The National Institute on Aging (NIA) Imbedded Pragmatic Alzheimer's disease (AD) and AD-Related Dementias (AD/ADRD) Clinical Trials (IMPACT) Collaboratory's Health Equity Team will contribute to the overall mission of the collaboratory by developing and implementing strategies to address health equity in the conduct of ePCTs and ensure the collaboratory is a national resource for all Americans with dementia. As a first step toward meeting these goals, this article reviews what is currently known about the inclusion of health disparities populations of people living with dementia (PLWD) and their caregivers in ePCTs, highlights unique challenges related to health equity in the conduct of ePCTs, and suggests priority areas in the design and implementation of ePCTs to increase the awareness and avoidance of pitfalls that may perpetuate and magnify healthcare disparities. J Am Geriatr Soc 68:S8-S13, 2020.

Incident prolonged QT interval in midlife and late-life cognitive performance.

BACKGROUND: Measures of cardiac ventricular electrophysiology have been associated with cognitive performance in cross-sectional studies. We sought to evaluate the association of worsening ventricular repolarization in midlife, as measured by incident prolonged QT interval, with cognitive decline in late life. METHODS: Midlife QT interval was assessed by electrocardiography during three study visits from 1965/68 to 1971/74 in a cohort of Japanese American men aged 46-68 at Exam 1 from the Honolulu Heart Study. We defined incident prolonged QT as the QT interval in the upper quartile at Exam 2 or 3 after QT interval in lower three quartiles at Exam 1. Cognitive performance was assessed at least once using the Cognitive Abilities Screening Instrument (CASI), scored using item response theory (CASI-IRT), during four subsequent visits from 1991/93 to 1999/2000 among 2,511 of the 4,737 men in the Honolulu-Asia Aging Study otherwise eligible for inclusion in analyses. We used marginal structural modeling to determine the association of incident prolonged QT with cognitive decline, using weighting to account for confounding and attrition. RESULTS: Incident prolonged QT interval in midlife was not associated with late-life CASI-IRT at cognitive baseline (estimated difference in CASI-IRT: 0.04; 95% CI: -0.28, 0.35; p = 0.81), or change in CASI-IRT over time (estimated difference in annual change in CASI-IRT: -0.002; 95%CI: -0.013, 0.010; p = 0.79). Findings were consistent across sensitivity analyses. CONCLUSIONS: Although many midlife cardiovascular risk factors and cardiac structure and function measures are associated with late-life cognitive decline, incident prolonged QT interval in midlife was not associated with late-life cognitive performance or cognitive decline.

Influence of culture and age on the self-reference effect.

Relating information to oneself can enhance memory for young and older adults. However, most studies investigating self-referencing have focused on Western populations, for whom the self is considered an independent and distinct entity. Whether self-referencing as a mnemonic strategy similarly benefits East Asians, cultures associated with interdependent self-construal, has been investigated little, particularly with age. In this study, we investigated the effect of self-reference on memory for both younger and older adults from American and Taiwanese cultures, predicting that self-referencing would be a less effective strategy for younger and older adults from Taiwan compared to Americans. Results reveal some cultural differences with age, with Taiwanese older adults benefitting less from self-referencing than younger Taiwanese, though the effect did not differ with age for Americans, or between younger adults across cultures. Thus, our results suggest that the potential mnemonic benefits of self-referencing may be limited in older adults from Eastern cultures.

Reduction of the Self-Reference Effect in Younger and Older Adults.

Relating information to the self improves memory. However, this self-reference effect (SRE) is typically studied through explicit self-judgments on individual trials. The current study assessed whether a self-referential mode of thought, induced through a writing task, also induced an SRE on a later task. The study also tested the effects of aging on the SRE, given that a long-lasting mnemonic strategy may be especially relevant for this group. Ninety-two younger adults and 60 older adults were assigned to different writing conditions and then completed an unrelated SRE task. Across younger and older adults, the classic SRE effect was observed in the narrative writing condition, reduced in the semantic self-reference condition, and further reduced in the episodic self-reference condition. These results support the induction of a self-referential mode of thought, but this mode does not enhance memory. The classic SRE effect can be reduced after thinking about the self by reflecting on autobiographical memories. Results argue for a single shared self-referential mechanism that can be accessed through self-focused writing or the classic SRE task.

Interactive Effects of Racial Identity and Repetitive Head Impacts on Cognitive Function, Structural MRI-Derived Volumetric Measures, and Cerebrospinal Fluid Tau and Aß.

BACKGROUND: Factors of increased prevalence among individuals with Black racial identity (e.g., cardiovascular disease, CVD) may influence the association between exposure to repetitive head impacts (RHI) from American football and later-life neurological outcomes. Here, we tested the interaction between racial identity and RHI on neurobehavioral outcomes, brain volumetric measures, and cerebrospinal fluid (CSF) total tau (t-tau), phosphorylated tau (p-tau181), and Aß1 - 42 in symptomatic former National Football League (NFL) players. METHODS: 68 symptomatic male former NFL players (ages 40-69; n = 27 Black, n = 41 White) underwent neuropsychological testing, structural MRI, and lumbar puncture. FreeSurfer derived estimated intracranial volume (eICV), gray matter volume (GMV), white matter volume (WMV), subcortical GMV, hippocampal volume, and white matter (WM) hypointensities. Multivariate generalized linear models examined the main effects of racial identity and its interaction with a cumulative head impact index (CHII) on all outcomes. Age, years of education, Wide Range Achievement Test, Fourth Edition (WRAT-4) scores, CVD risk factors, and APOEε4 were included as covariates; eICV was included for MRI models. P-values were false discovery rate adjusted. RESULTS: Compared to White former NFL players, Black participants were 4 years younger (p = 0.04), had lower WRAT-4 scores (mean difference = 8.03, p = 0.002), and a higher BMI (mean difference = 3.09, p = 0.01) and systolic blood pressure (mean difference = 8.15, p = 0.03). With regards to group differences on the basis of racial identity, compared to White former NFL players, Black participants had lower GMV (mean adjusted difference = 45649.00, p = 0.001), lower right hippocampal volume (mean adjusted difference = 271.96, p = 0.02), and higher p-tau181/t-tau ratio (mean adjusted difference = -0.25, p = 0.01). There was not a statistically significant association between the CHII with GMV, right hippocampal volume, or p-tau181/t-tau ratio. However, there was a statistically significant Race x CHII interaction for GMV (b = 2206.29, p = 0.001), right hippocampal volume (b = 12.07, p = 0.04), and p-tau181/t-tau ratio concentrations (b = -0.01, p = 0.004). CONCLUSION: Continued research on racial neurological disparities could provide insight into risk factors for long-term neurological disorders associated with American football play.

Mind-wandering in healthy aging and early stage Alzheimer's disease.

OBJECTIVE: The frequency of mind-wandering (MW) decreases as a function of age in healthy individuals. One possible explanation is that MW is a resource-dependent process, and cognitive resources decline with age. The present study provides the first investigation of MW in the earliest stages of Alzheimer's disease (AD) to further examine the resource model and discontinuities between healthy aging and AD. METHOD: Three large cohorts completed the Sustained Attention to Response Task (SART): a healthy middle-aged group (mean age = 61.79 ± 5.84 years; N = 270), a healthy older adult group (mean age = 76.58 ± 5.27 years; N = 282), and a group with early stage AD (mean age = 76.08 ± 7.17; N = 77), comparable in age to the second group. RESULTS: Self-reports of MW during the SART decreased as a function of age, and there was a further decrease in the AD group. All 3 groups produced faster responses on trials before No-Go errors, suggesting MW occurred in all cohorts. After No-Go errors, healthy older adults slowed disproportionately compared with middle-aged adults. This was not evident in AD individuals who showed posterror slowing comparable with that in the middle-aged group. CONCLUSIONS: The decreased self-reported MW in older adults and the further decline in AD are consistent with the cognitive resource account of MW. Behavioral indices suggest that AD is on a continuum with healthy aging, with the exception of posterror slowing that may suggest performance monitoring deficits in early AD individuals (e.g., lack of error awareness). (PsycINFO Database Record

Subjective cognitive concerns are associated with objective memory performance in Caucasian but not African-American persons.

Objective: subjective cognitive concerns (SCC) have been proposed as a means of identifying individuals at risk for Alzheimer's disease (AD). However, the utility of SCCs has not been well-explored for African-Americans, who are twice as likely to develop AD dementia as Caucasians. We investigated whether race affects the association between SCCs and objective memory performance. Methods: we used a composite of three SCC questionnaires, and three challenging episodic memory tests. We studied 289 (61% female; African-American n = 47) clinically normal older individuals. Two hierarchical linear regressions assessed the modifying role of race on the association between SCC and objective memory performance. The first regression was conducted on the full sample, while the second matched the racial groups on age, estimated verbal IQ and socioeconomic status. Results: in the full sample, both groups reported similar levels of SCCs, P = 0.10, although African-Americans performed worse on the memory tasks, P < 0.001. No group differences were observed in the matched sample. The SCC × race interaction term was nonsignificant in the full sample, ß = 0.109, P = 0.09, but was significant in the matched sample, ß = 0.422, P = 0.037. While a significant correlation was observed between SCCs and memory among Caucasians, r = -0.401, the correlation was not found among African-Americans, r = -0.052. Conclusions: results suggest that the dissociation between SCCs and memory performance in African-Americans may indicate qualitative differences in how diverse groups endorse cognitive concerns, even after considering socioeconomic and educational factors.

Region-Specific Association of Subjective Cognitive Decline With Tauopathy Independent of Global ß-Amyloid Burden.

Importance: The ability to explore associations between reports of subjective cognitive decline (SCD) and biomarkers of early Alzheimer disease (AD) pathophysiologic processes (accumulation of neocortical ß-amyloid [Aß] and tau) provides an important opportunity to understand the basis of SCD and AD risk. Objective: To examine associations between SCD and global Aß and tau burdens in regions of interest in clinically healthy older adults. Design, Setting, and Participants: This imaging substudy of the Harvard Aging Brain Study included 133 clinically healthy older participants (Clinical Dementia Rating Scale global scores of 0) participating in the Harvard Aging Brain Study who underwent cross-sectional flortaucipir F 18 (previously known as AV 1451, T807) positron emission tomography (FTP-PET) imaging for tau and Pittsburgh compound B carbon 11-labeled PET (PiB-PET) imaging for Aß. The following 2 regions for tau burden were identified: the entorhinal cortex, which exhibits early signs of tauopathy, and the inferior temporal region, which is more closely associated with AD-related pathologic mechanisms. Data were collected from June 11, 2012, through April 7, 2016. Main Outcomes and Measures: Subjective cognitive decline was measured using a previously published method of z-transforming subscales from the Memory Functioning Questionnaire, the Everyday Cognition battery, and a 7-item questionnaire. The Aß level was measured according to a summary distribution volume ratio of frontal, lateral temporal and parietal, and retrosplenial PiB-PET tracer uptake. The FTP-PET measures were computed as standardized uptake value ratios. Linear regression models focused on main and interactive effects of Aß, entorhinal cortical, and inferior temporal tau on SCD, controlling for age, sex, educational attainment, and Geriatric Depression Scale score. Results: Of the 133 participants, 75 (56.3%) were women and 58 (43.6%) were men; mean (SD) age was 76 (6.9) years (range, 55-90 years). Thirty-nine participants (29.3%) exhibited a high Aß burden. Greater SCD was associated with increasing entorhinal cortical tau burden (ß = 0.35; 95% CI, 0.19-.52; P < .001) and Aß burden (ß = 0.24; 95% CI, 0.08-.40; P = .005), but not inferior temporal tau burden (ß = 0.10; 95% CI, -0.08 to 0.28; P = .27). This association between entorhinal cortical tau burden and SCD was largely unchanged after accounting for Aß burden (ß = 0.36; 95% CI, 0.15-.58; P = .001), and no interaction influenced SCD (ß = -0.36; 95% CI, -0.34 to 0.09; P = .25). An exploratory post hoc whole-brain analysis also indicated that SCD was predominantly associated with greater tau burden in the entorhinal cortex. Conclusions and Relevance: Subjective cognitive decline is indicative of accumulation of early tauopathy in the medial temporal lobe, specifically in the entorhinal cortex, and to a lesser extent, elevated global levels of Aß. Our findings suggest multiple underlying pathways that motivate SCD that do not necessarily interact to influence SCD endorsement. As such, multiple biological factors must be considered when assessing SCD in clinically healthy older adults.

The influence of demographic factors on subjective cognitive concerns and beta-amyloid.

BACKGROUND: Converging evidence suggests that subjective cognitive concerns (SCC) are associated with biomarker evidence of Alzheimer's disease (AD) prior to objective clinical impairment. However, the sensitivity of SCC reports in early AD may be biased by demographic factors. Here, we sought to investigate whether age, education, and sex influence the relationship between SCC and amyloid (Aß) burden. METHODS: In this cross-sectional study, we examined 252 clinically normal (CN) individuals (57.7% females) enrolled in the Harvard Aging Brain Study, ages 63-90 years (mean 73.7±6) with 6-20 years of education (mean 15.8±3). SCC was assessed as a composite score comprising three questionnaires. Cortical Aß burden was assessed with Pittsburgh compound B positron emission tomography imaging. A series of linear regression models assessed the potential modifying role of demographic variables with respect to Aß burden and SCC. A post-hoc mediation model was implemented to further understand the relationship between Aß burden and SCC via their relationship with education. RESULTS: Age (ß = -0.84, p = 0.36) and sex (ß = -0.55, p = 0.22) did not modify the relationship between SCC and Aß burden. Fewer years of education was correlated with greater SCC (r = -0.12, p = 0.05), but the relationship between Aß burden and SCC was stronger in those with more education (ß = 1.16, p < 0.05). A partial mediation effect was found of Aß burden on SCC via education (b = -0.12, 95% CI [-0.31, -0.02]). CONCLUSIONS: These findings suggest that the association between SCC and Aß burden becomes stronger with greater educational attainment. Thus, SCC may be of particular importance in highly educated CN individuals harboring amyloid pathology.

Shaping the Future of Research: a perspective from junior scientists.

The landscape of scientific research and funding is in flux as a result of tight budgets, evolving models of both publishing and evaluation, and questions about training and workforce stability. As future leaders, junior scientists are uniquely poised to shape the culture and practice of science in response to these challenges. A group of postdocs in the Boston area who are invested in improving the scientific endeavor, planned a symposium held on October 2 (nd) and 3 (rd), 2014, as a way to join the discussion about the future of US biomedical research. Here we present a report of the proceedings of participant-driven workshops and the organizers' synthesis of the outcomes.

Can mind-wandering be timeless? Atemporal focus and aging in mind-wandering paradigms.

Recent research has examined how often mind-wandering occurs about past vs. future events. However, mind-wandering may also be atemporal, although previous investigations of this possibility have not yielded consistent results. Indeed, it is unclear what proportion of mind-wandering is atemporal, and also how an atemporal response option would affect the future-oriented bias often reported during low-demand tasks used to measure mind-wandering. The present study examined self-reported (Experiment 1) and probe-caught (Experiment 2) mind-wandering using the low-demand Sustained Attention to Response Task (SART) in younger (18-30) and older (50-73) adults in an experimental paradigm developed to measure mind-wandering using Amazon's Mechanical Turk (Mturk). Across self-reported and probe-caught mind-wandering, the atemporal response option was used at least as frequently as past or future mind-wandering options. Although older adults reported far fewer mind-wandering events, they showed a very similar temporal pattern to younger adults. Most importantly, inclusion of the atemporal report option affected performance on the SART and selectively eliminated the prospective bias in self-reported mind-wandering, but not in probe-caught mind-wandering. These results suggest that both young and older participants are often not thinking of past or future events when mind-wandering, but are thinking of events that cannot easily be categorized as either.

Age-related changes in attentional selection: quality of task set or degradation of task set across time?

The present study explores the nature of attentional selection in younger and older adults. Following R. De Jong, E. Berendsen, and R. Cools (1999, Acta Psychologica, Vol. 101, pp. 379-394), we manipulated the response to stimulus interval (RSI) in two attentional selection paradigms to examine if there are age-related differences in the quality of task set and/or the maintenance of task set across time. In Experiment 1, we found that the interference effect in a spatial interference task was (a) overall larger in older adults compared with younger adults, and (b) smaller at the short RSI (200 ms) compared with the long RSI (2000 ms), and (c) not associated with an interaction between age and RSI. The second experiment explored the same variables in a Stroop color interference paradigm. Again, older adults produced a disproportionately larger interference effect than younger adults, the interference effect was smaller at the short RSI compared with the long RSI, and there was no evidence of an interaction between age and RSI. In both experiments, the larger interference effect could not be attributed to age-related general slowing and there was evidence from Vincentile analyses of increasing interference and age effects at the slower response latencies. These results indicate that attentional selection deficits in these two experiments were due to a breakdown in the quality of the task set as opposed to age-related differences in the maintenance of the task set across time.