Data stewardship in FTLD research: Investigator and research participant views.

INTRODUCTION: Federal policies and guidelines have expanded the return of individual results to participants and expectations for data sharing between investigators and through repositories. Here, we report investigators' and study participants' views and experiences with data stewardship practices within frontotemporal lobal degeneration (FTLD) research, which reveal unique ethical challenges. METHODS: Semi-structured interviews with (1) investigators conducting FTLD research that includes genetic data collection and/or analysis and (2) participants enrolled in a single site longitudinal FTLD study. RESULTS: Analysis of the interviews identified three meta themes: perspectives on data sharing, experiences with enrollment and participation, and data management and security as mechanisms for participant protections. DISCUSSION: This study identified a set of preliminary gaps and needs regarding data stewardship within FTLD research. The results offer initial insights on ethical challenges to data stewardship aimed at informing future guidelines and policies.

Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases.

Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer's disease based on inferred underlying histopathology. Parkinson's disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington's disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned-more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers-we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.

Crime, Incarceration, and Dementia: An Aging Criminal System.

Dementia within the criminal system, from arrest through incarceration, has been largely ignored. While the health system has begun grappling with the chronic conditions that will accompany an aging society, the criminal system has yet to meaningfully respond. Dementia is a clinical syndrome characterized by impairment in cognitive domains (memory, executive function, visuospatial). Additionally, dementia often includes behavioral symptoms that increase the likelihood that an individual's actions may violate social norms and in some circumstances be deemed criminal. Prior studies have established criminal behavior as a trend among individuals living with dementia. Yet, the criminal system has yet to establish protections for individuals who commit a crime while impaired by dementia. This paper will report on an empirical study to evaluate the treatment of persons with dementia within the criminal justice system. We will report on interviews with attorneys (n=15) regarding their experience and perspective on the treatment of persons with dementia post-arrest. In the paper, we will explore topics identified through these interviews including pre-trial release, competency, placement (housing), criminal liability determination, sentencing, and post-conviction release. We will highlight key findings including the lack of a systematic screening process for dementia post-arrest, placement is a significant challenge, attorneys' lack of training on dementia to be able to understand how the disease could impact decision-making, and the two legal mechanisms available to divert miss the mark given their focus on psychiatric populations. We will use these data and findings to argue for a research and policy agenda to address a gap in legal policies to appropriately manage persons with dementia post-arrest.

Private payer coverage policies for ApoE-e4 genetic testing.

PURPOSE: ApoE-e4 has a well-established connection to late-onset Alzheimer disease (AD) and is available clinically. Yet, there have been no analyses of payer coverage policies for ApoE. Our objective was to analyze private payer coverage policies for ApoE genetic testing, examine the rationales, and describe supporting evidence referenced by policies. METHODS: We searched for policies from the eight largest private payers (by member numbers) covering ApoE testing for late-onset AD. We implemented content analysis methods to evaluate policies for coverage decisions and rationales. RESULTS: Seven payers had policies with positions on ApoE testing. Five explicitly state they do not cover ApoE and two apply generic preauthorization criteria. Rationales supporting coverage decisions include: reference to guidelines or national standards, inadequate data supporting testing, characterizing testing as investigational, or that testing would not alter patients' clinical management. CONCLUSION: Seven of the eight largest private payers' coverage policies reflect standards that discourage ApoE testing due to a lack of clinical utility. As the field advances, ApoE testing may have an important clinical role, particularly considering that disease-modifying therapies are under evaluation by the US Food and Drug Administration. These types of field advancements may not be consistent with private payers' policies and may cause payers to reevaluate existing coverage policies.

Stakeholders' Perspectives on Preclinical Testing for Alzheimer's Disease.

BACKGROUND AND AIMS: Progress towards validating amyloid beta as an early indicator of Alzheimer's disease (AD) heightens the need for evaluation of stakeholders' perspectives of the benefits and harms of preclinical testing in asymptomatic individuals. METHODS: Investigators conducted and analyzed 14 semi-structured interviews with family members of patients diagnosed with AD. RESULTS: Participants reported benefits, including the potential to seek treatment, make lifestyle changes, and prepare for cognitive impairment. Participants identified harms, including social harms, adverse life decisions, and psychological harms. Nine participants reported either a "positive global perspective" or a "positive global perspective (qualified)." CONCLUSION: Results from this study characterized stakeholders' perspectives on the potential benefits and harms of clinical use of preclinical testing for AD. Investigators used data from this study to develop a framework that contributes to ongoing discussions that will evaluate widespread adoption of preclinical testing and will inform future research.

Integrating Public Health Ethics into Public Health Policymaking: Being in the Room Where It Happens.

This commentary takes up a challenge posed by Franklin Miller in a 2022 essay in Bioethics Forum. Dr. Miller queried whether bioethicists could be useful in public health policy contexts and while he refrained from issuing an ultimate opinion, did identify several challenges to such utility. The current piece responds to the challenges Dr. Miller identifies and argues that with appropriate training, public health ethicists can be of service in virtually any context in which public health policies are deliberated and decided.

Out-of-Pocket Expenses for Long-Term Care by Dementia Status and Residential Setting among US Older Adults.

OBJECTIVE: To examine long-term care out-of-pocket payments by dementia status and residential setting. DESIGN: Compare monthly out-of-pocket long-term care expenses paid to facilities and helpers, total monthly out-of-pocket long-term expenses and as a percentage of monthly income by dementia status and residential status (community, residential facility, and nursing home). SETTING AND PARTICIPANTS: US Nationwide, 2019 National Health and Aging Trends Study (NHATS) respondents aged ≥70 years. METHODS: We analyzed respondent-level data from the nationally representative 2019 NHATS. Weighted descriptive statistics were calculated for long-term care payments by source and summarized by dementia status and the respondent's residential status. RESULTS: Among 4505 respondents aged ≥70 years, 1750 (38.8%) had possible or probable dementia and 2755 (61.2%) had no dementia. The median monthly out-of-pocket long-term care expenses for persons with dementia was $1465 for those living in nursing homes, and $2925 for those living in other residential facilities, much higher than those with dementia living in the community ($260). Although these are similar to the median out-of-pocket payments for persons without dementia by setting, those with dementia were at greater risk of facing catastrophic out-of-pocket expenses for long-term care than those without dementia, with the 75th percentile value of out-of-pocket payment at $4566 among dementia adults living in non-nursing home residential care facilities, and $7500 for those in nursing homes, compared to $3694 and $3100 among those without dementia. At median, these expenses accounted for 100% of monthly income of respondents with dementia living in facilities. CONCLUSIONS AND IMPLICATIONS: Persons with dementia living in facilities often face substantial financial burdens from high out-of-pocket long-term care expenses. Policies that provide sufficient financial assistance are needed to address long-term care-related financial burdens experienced by older adults and their families, especially for those with dementia.

Creating an Unprotected Class: Addressing Legal Risks in the Era of Biologically-Defined Alzheimer's Disease.

Background: Documentation of preclinical biomarker tests for Alzheimer's disease (AD) in the medical record may expose patients to employment and insurance discrimination risks. There is a gap in research describing clinicians' approaches to documenting biomarker results. Objective: To evaluate discrimination risks faced by patients undergoing biomarker testing for AD through a qualitative analysis of clinician documentation practices. Methods: Semi-structured interviews using hypothetical patient scenarios. The qualitative analysis focused on interviewees' responses related to documentation and disclosure of results. Results: We collected and analyzed 17 interviews with dementia experts; and identified three approaches to documenting biomarkers as: an association with active AD, noninformative, and an increased susceptibility for AD. Those who associated biomarkers with active disease were more likely to favor disclosure to employers and insurers, which could increase discrimination risks. Conclusions: This study demonstrates the variety of documentation and disclosure practices likely to emerge for preclinical AD biomarker tests and highlights a need for guidelines in this area.

The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology.

Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.

A time to step in: legal mechanisms for protecting those with declining capacity.

Current estimates approximate that the population over sixty-five years of age will increase from 40 million in 2010 to 72.1 million by 2030. As society ages, the number of elderly with cognitive deficits that impair decision-making abilities will also increase. This will place additional burdens on families and probate courts seeking to balance individual autonomy with necessary protections. A legal determination of incompetency is a prerequisite to a judicial order appointing a guardianship or other protective mechanism. The current legal-medical model for competency determinations fails to reflect the complexities of declining capacity in an aging population. A global structure for competency determinations leaves a critical gap between competent and incompetent. The gap between competence and incompetence not only raises concerns about how to classify those that fall between the two, but also highlights the lack of legal protections for those within the gap. A revised model is needed to provide protections to individuals who do not yet meet the threshold for incompetence but require additional protections for their personal or financial welfare. This Article provides an unprecedented examination of the legal model for determining competence through a comparison of the medical model for evaluating capacity. While a number of legal scholars have examined the appointment and oversight of guardians, fewer articles have critically examined the process by which individuals are declared incompetent. This Article presents a comprehensive overview of competency and clinical capacity determination procedures, legal mechanisms available to protect individuals with declining capacity, and policy recommendations for improving legal protections in light of inefficiencies related to legal competency determinations.

Forgotten and without Protections: Older Adults in Prison Settings.

The number of older adults incarcerated in prisons is growing significantly, and there is a great need for legal authority, processes, and resources to mitigate individual and social burdens of elder neglect and abuse within these settings. Older adults in prison may be particularly vulnerable to abuse, neglect, or exploitation. They are dependent on the carceral system for basic resources, are at risk for retaliatory actions for reporting mistreatment, and bear disproportionately high health burdens. This essay first considers standards and resources for mitigating elder mistreatment in the community and residential-care settings in contrast to the available resources in prisons. Arguing that a conceptual model of elder abuse tailored to the prison population is needed, the essay proposes a research agenda through which such a model could be developed. The model could then be used in the creation of policy for detecting and mitigating elder mistreatment of incarcerated people. The essay concludes with a call to action to address the rift in legal protections and processes that leave older adults in prison at increased risk of abuse and neglect without a clear pathway for recourse.

Geriatricians' Perspectives on the Multiple Dimensions of Utility of Genetic Testing for Alzheimer's Disease: A Qualitative Study.

BACKGROUND: Research advancements in Alzheimer's disease (AD) raise opportunities for genetic testing to improve diagnostic and risk assessment. Despite emerging developments, it is unclear how geriatricians perceive the potential clinical and personal utility of genetic testing for their patients. Geriatricians' perspectives are essential to understanding potential ethical, policy, and clinical challenges. OBJECTIVE: In this paper, we report on geriatricians' perspectives on the utility of genetic testing for AD. METHODS: Semi-structured interviews with California geriatricians within different practices settings to collect and characterize their perspectives on genetic testing for AD. We used an adapted grounded theory approach to analyze recorded and transcribed interviews. RESULTS: We identified geriatricians' (n = 10) perspectives on the clinical and personal utility of testing, alongside their views on clinical care approaches for older adults. Geriatricians perceived minimal clinical utility of genetic testing for AD, though that may change with the availability of disease-modifying therapies. Yet, they recognized the potential personal utility of testing (e.g., assisting with future financial planning). Finally, geriatricians expressed concerns regarding patients' anxiety from learning about genetic status, particularly through direct-to-consumer (DTC) testing. CONCLUSION: Our data highlight that the decision to order genetic testing requires clinical and ethical considerations, including balancing limited clinical utility with the potential personal utility. Although DTC testing is available, geriatricians perceive that they have an important role in managing the decision to test and interpreting the results. Further research is needed to inform policy and ethical guidelines to support geriatricians' critical role to counsel patients considering clinical and DTC genetic testing.

The Advisory Group on Risk Evidence Education for Dementia: Multidisciplinary and Open to All.

The brain changes of Alzheimer's disease and other degenerative dementias begin long before cognitive dysfunction develops, and in people with subtle cognitive complaints, clinicians often struggle to predict who will develop dementia. The public increasingly sees benefits to accessing dementia risk evidence (DRE) such as biomarkers, predictive algorithms, and genetic information, particularly as this information moves from research to demonstrated usefulness in guiding diagnosis and clinical management. For example, the knowledge that one has high levels of amyloid in the brain may lead one to seek amyloid reducing medications, plan for disability, or engage in health promoting behaviors to fight cognitive decline. Researchers often hesitate to share DRE data, either because they are insufficiently validated or reliable for use in individuals, or there are concerns about assuring responsible use and ensuring adequate understanding of potential problems when one's biomarker status is known. Concerns include warning people receiving DRE about situations in which they might be compelled to disclose their risk status potentially leading to discrimination or stigma. The Advisory Group on Risk Evidence Education for Dementia (AGREEDementia) welcomes all concerned with how best to share and use DRE. Supporting understanding in clinicians, stakeholders, and people with or at risk for dementia and clearly delineating risks, benefits, and gaps in knowledge is vital. This brief overview describes elements that made this group effective as a model for other health conditions where there is interest in unfettered collaboration to discuss diagnostic uncertainty and the appropriate use and communication of health-related risk information.

A Qualitative Analysis of Ethical Perspectives on Recruitment and Consent for Human Intracranial Electrophysiology Studies.

Intracranial electrophysiological research methods, including those applying electrodes on the cortical surface or in deep structures, have become increasingly important in human neuroscience. They also pose novel ethical concerns, as human studies require the participation of neurological patients undergoing surgery for conditions such as epilepsy and Parkinson's disease. Research participants in this setting may be vulnerable to conflicts of interest, therapeutic misconception, and other threats to valid recruitment and consent. We conducted semi-structured interviews with investigators from NIH-funded studies involving recording or stimulation inside the human skull. We elicited perspectives on study recruitment and consent procedures, and analyzed transcripts using a modified grounded theory approach. We interviewed 26 investigators from 19 separate intracranial electrophysiology studies, who described two study types: opportunity studies (n = 15) and experimental trials (n = 4). Respondents described significant heterogeneity in recruitment and consent procedures, even among studies employing similar techniques. In some studies, clinician-investigators were specifically barred from obtaining consent, while in other studies clinician-investigators were specifically required to obtain consent; regulatory guidance was inconsistent. Respondents also described various models for subject selection, the timing of consent, and continuing consent for temporally extended studies. Respondents expressed ethical concerns about participants' vulnerability and the communication of research-related risks. We found a lack of consensus among investigators regarding recruitment and consent methods in human intracranial electrophysiology. This likely reflects the novelty and complexity of such studies and indicates a need for further discussion and development of best practices in this research domain.

A Matter of Intent: A Social Obligation to Improve Criminal Procedures for Individuals with Dementia.

The relationship between dementia and criminal behavior perplexes legal and health care systems. Dementia is a progressive clinical syndrome defined by impairment in at least two cognitive domains that interferes with one's activities of daily. Dementia symptoms have been associated with behaviors that violate social norms and constitute criminal actions. A failure to address a gap in policies that support appropriate management of individuals with dementia reflects a failure in our social obligation to care for those who are most vulnerable amongst us. Categorical protections, informed by precedent models applied to juveniles and individuals with psychiatric illness, could help meet a social obligation to provide protections to individuals with dementia. We propose an approach that integrates affirmative defenses to mitigate criminal liability and sentencing restrictions to prevent cruel and unusual punishment.

Alzheimer's disease biomarkers: another tool for FAA pilot screening?

Research advancements to improve the accuracy of diagnosing Alzheimer's disease (AD) have altered clinicians and researchers' understanding of the disease process. The discovery of amyloid and tau biomarkers as measures of disease pathology supports early identification of disease risk that precedes symptom onset. As a result, AD is now understood to be an underlying pathology that causes a spectrum of clinical syndromes, beginning with preclinical AD. Future clinical implementation of biomarkers will raise novel employment and professional licensure discrimination risks based on AD biomarker status. This article evaluates the potential consequences of biomarker status for commercial pilots within Federal Aviation Administration pilot licensing procedures. The article argues for a careful implementation of AD biomarker status in licensing procedures to emphasize public safety, integrate accurate scientific knowledge, and limit unjustified and adverse consequences for individual pilots.

Direct to Consumer Biomarker Testing for Alzheimer Disease-Are We Ready for the Insurance Consequences?

This Viewpoint discusses direct-to-consumer biomarker tests for Alzheimer disease and their implications on future insurance coverage.

Concussion reporting and perceived knowledge of professional fighters.

Objective: For concussions to be effectively managed in sports, they need to be correctly identified and reported. The extent to which professional athletes correctly recognize concussions, and their willingness to report symptoms, is not yet well understood. Given the risk of head injuries leading to concussions across combat sports, insight into professional fighters' knowledge and reporting of concussive symptoms is essential to improve concussion management. Methods: To investigate understanding and reporting patterns of concussions sustained while training or competing, 257 fighters completed a self-report questionnaire assessing self-perception of concussion knowledge, trust of ringside medical providers, and reported number of previous head injuries. Fighting history, including number of knockouts, was obtained from self-report (amateur) and published (professional) records. Results: Significant gaps in fighters' perceived knowledge of concussion symptoms and long-term effects of multiple concussions emerged. Approximately 40% of fighters reported returning to training or competition the same day a head injury was sustained, while 21% of fighters endorsed concealing symptoms of head injury from medical providers and coaches. Conclusions: Confusion surrounding terms used to describe head injuries amongst fighters (e.g., concussions, knockouts), coupled with limited understanding of concussive symptoms and a desire to return to competition, likely contributes to significant underreporting of symptoms.