Putting participants and study partners FIRST when clinical trials end early.

Between 2018 and 2019, multiple clinical trials ended earlier than planned, resulting in calls to improve communication with and support for participants and their study partners ("dyads"). The multidisciplinary Participant Follow-Up Improvement in Research Studies and Trials (Participant FIRST) Work Group met throughout 2021. Its goals were to identify best practices for communicating with and supporting dyads affected by early trial stoppage. The Participant FIRST Work Group identified 17 key recommendations spanning the pre-trial, mid-trial, and post-trial periods. These focus on prospectively allocating sufficient resources for orderly closeout; developing dyad-centered communication plans; helping dyads build and maintain support networks; and, if a trial stops, informing dyads rapidly. Participants and study partners invest time, effort, and hope in their research participation. The research community should take intentional steps toward better communicating with and supporting participants when clinical trials end early. The Participant FIRST recommendations are a practical guide for embarking on that journey.

Risk of Transmissibility From Neurodegenerative Disease-Associated Proteins: Experimental Knowns and Unknowns.

Recent studies in animal models demonstrate that certain misfolded proteins associated with neurodegenerative diseases can support templated misfolding of cognate native proteins, to propagate across neural systems, and to therefore have some of the properties of classical prion diseases like Creutzfeldt-Jakob disease. The National Institute of Aging convened a meeting to discuss the implications of these observations for research priorities. A summary of the discussion is presented here, with a focus on limitations of current knowledge, highlighting areas that appear to require further investigation in order to guide scientific practice while minimizing potential exposure or risk in the laboratory setting. The committee concluded that, based on all currently available data, although neurodegenerative disease-associated aggregates of several different non-prion proteins can be propagated from humans to experimental animals, there is currently insufficient evidence to suggest more than a negligible risk, if any, of a direct infectious etiology for the human neurodegenerative disorders defined in part by these proteins. Given the importance of this question, the potential for noninvasive human transmission of proteopathic disorders is deserving of further investigation.

Maximizing Safety in the Conduct of Alzheimer's Disease Fluid Biomarker Research in the Era of COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic led to an abrupt halt of many Alzheimer's disease (AD) research studies at sites spanning the world. This is especially true for studies requiring in-person contact, such as studies collecting biofluids. Since COVID-19 is likely to remain a threat for an extended period, the resumption of fluid biomarker studies requires the development and implementation of procedures that minimize the risk of in-person visits to participants, staff, and individuals handling the biofluid samples. Some issues to consider include structuring the visit workflow to minimize contacts and promote social distancing; screening and/or testing participants and staff for COVID-19; wearing masks and performing hand hygiene; and precautions for handling, storing, and analyzing biofluids. AD fluid biomarker research remains a vitally important public health priority and resuming studies requires appropriate safety procedures to protect research participants and staff.

The Collaborative Aging Research Using Technology Initiative: An Open, Sharable, Technology-Agnostic Platform for the Research Community.

INTRODUCTION: Future digital health research hinges on methodologies to conduct remote clinical assessments and in-home monitoring. The Collaborative Aging Research Using Technology (CART) initiative was introduced to establish a digital technology research platform that could widely assess activity in the homes of diverse cohorts of older adults and detect meaningful change longitudinally. This paper reports on the built end-to-end design of the CART platform, its functionality, and the resulting research capabilities. METHODS: CART platform development followed a principled design process aiming for scalability, use case flexibility, longevity, and data privacy protection while allowing sharability. The platform, comprising ambient technology, wearables, and other sensors, was deployed in participants' homes to provide continuous, long-term (months to years), and ecologically valid data. Data gathered from CART homes were sent securely to a research server for analysis and future data sharing. RESULTS: The CART system was created, iteratively tested, and deployed to 232 homes representing four diverse cohorts (African American, Latinx, low-income, and predominantly rural-residing veterans) of older adults (n = 301) across the USA. Multiple measurements of wellness such as cognition (e.g., mean daily computer use time = 160-169 min), physical mobility (e.g., mean daily transitions between rooms = 96-155), sleep (e.g., mean nightly sleep duration = 6.3-7.4 h), and level of social engagement (e.g., reports of overnight visitors = 15-45%) were collected across cohorts. CONCLUSION: The CART initiative resulted in a minimally obtrusive digital health-enabled system that met the design principles while allowing for data capture over extended periods and can be widely used by the research community. The ability to monitor and manage health digitally within the homes of older adults is an important alternative to in-person assessments in many research contexts. Further advances will come with wider, shared use of the CART system in additional settings, within different disease contexts, and by diverse research teams.

Population Health Solutions for Assessing Cognitive Impairment in Geriatric Patients.

In December 2017, the National Academy of Neuropsychology convened an interorganizational Summit on Population Health Solutions for Assessing Cognitive Impairment in Geriatric Patients in Denver, Colorado. The Summit brought together representatives of a broad range of stakeholders invested in the care of older adults to focus on the topic of cognitive health and aging. Summit participants specifically examined questions of who should be screened for cognitive impairment and how they should be screened in medical settings. This is important in the context of an acute illness given that the presence of cognitive impairment can have significant implications for care and for the management of concomitant diseases as well as pose a major risk factor for dementia. Participants arrived at general principles to guide future screening approaches in medical populations and identified knowledge gaps to direct future research. Key learning points of the summit included: recognizing the importance of educating patients and healthcare providers about the value of assessing current and baseline cognition;emphasizing that any screening tool must be appropriately normalized and validated in the population in which it is used to obtain accurate information, including considerations of language, cultural factors, and education; andrecognizing the great potential, with appropriate caveats, of electronic health records to augment cognitive screening and tracking of changes in cognitive health over time.

Alzheimer's Disease-Related Dementias Summit 2016: National research priorities.

Goal 1 of the National Plan to Address Alzheimer's Disease is to prevent and effectively treat Alzheimer disease and Alzheimer disease-related dementias by 2025. To help inform the research agenda toward achieving this goal, the NIH hosts periodic summits that set and refine relevant research priorities for the subsequent 5 to 10 years. This proceedings article summarizes the 2016 Alzheimer's Disease-Related Dementias Summit, including discussion of scientific progress, challenges, and opportunities in major areas of dementia research, including mixed-etiology dementias, Lewy body dementia, frontotemporal degeneration, vascular contributions to cognitive impairment and dementia, dementia disparities, and dementia nomenclature.

Recommendations of the Alzheimer's disease-related dementias conference.

The National Alzheimer's Project Act, signed into law in 2011, mandates a National Plan to Address Alzheimer's Disease that is updated annually. In the Plan, the term Alzheimer disease includes not only Alzheimer disease (AD) proper, but also several specified related dementias, namely, frontotemporal, Lewy body, vascular, and mixed dementia. In response to a specific action item in the 2012 National Plan, the National Institute of Neurological Disorders and Stroke, in collaboration with the National Institute on Aging, convened panels of experts and conducted a 2-day public conference to develop research priorities and timelines for addressing Alzheimer disease-related dementias (ADRD) in 5 topic areas: multiple etiology dementias, health disparities, Lewy body dementias including dementia with Lewy bodies and Parkinson disease dementia, frontotemporal dementia and related tauopathies, and vascular contributions to ADRD. By design, the product was up to 8 prioritized research recommendations in each topic area including estimated timelines from when work on a recommendation is started to completion or to full implementation of an ongoing activity, and recognition of shared research themes across recommendations. These included increased education and training of both researchers and health care professionals, addressing health disparities, fundamental neurobiology research, advanced diagnostics, collaborative biosample repositories, and a focus on developing effective interventions to prevent or treat ADRD by the year 2025 as targeted by the National Plan.

International Alzheimer's Disease Research Portfolio (IADRP) aims to capture global Alzheimer's disease research funding.

Alzheimer's disease (AD) is a recognized international public health crisis. There is an urgent need for public and private funding agencies around the world to coordinate funding strategies and leverage existing resources to enhance and expand support of AD research. To capture and compare their existing investments in AD research and research-related resources, major funding organizations are starting to utilize the Common Alzheimer's Disease Research Ontology (CADRO) to categorize their funding information. This information is captured in the International Alzheimer's Disease Research Portfolio (IADRP) for further analysis. As of January, 2014, over fifteen organizations from the US, Canada, Europe and Australia have contributed their information. The goal of the IADRP project is to enable funding organizations to assess the changing landscape of AD research and coordinate strategies, leverage resources, and avoid duplication of effort.

Obstacles and opportunities in Alzheimer's clinical trial recruitment.

The 2012 National Plan to Address Alzheimer's Disease set an ambitious goal: to both prevent and effectively treat Alzheimer's disease by 2025. To reach this goal, tens of thousands of volunteers will be needed to participate in clinical trials to test promising new interventions and therapies. To mobilize these volunteers and their health care providers to participate in future clinical trials, it will be necessary to achieve a better understanding of the barriers keeping people from participating in Alzheimer's research; form innovative partnerships among researchers, health care and social service providers, and the public; and develop more-effective outreach strategies. In this article we explore recruitment issues, including those unique to Alzheimer's studies, and we suggest concrete steps such as establishing a structured consortium linking all of the registries of Alzheimer's trials and establishing new partnerships with community and local organizations that can build trust and understanding among patients, caregivers, and providers.

Common Alzheimer's Disease Research Ontology: National Institute on Aging and Alzheimer's Association collaborative project.

Alzheimer's disease is recognized as a public health crisis worldwide. As public and private funding agencies around the world enhance and expand their support of Alzheimer's disease research, there is an urgent need to coordinate funding strategies and leverage resources to maximize the impact on public health and avoid duplication of effort and inefficiency. Such coordination requires a comprehensive assessment of the current landscape of Alzheimer's disease research in the United States and internationally. To this end, the National Institute on Aging at the National Institutes of Health and the Alzheimer's Association developed the Common Alzheimer's Disease Research Ontology (CADRO) as a dynamic portfolio analysis tool that can be used by funding agencies worldwide for strategic planning and coordination.

Assessment of cognition in early dementia.

Better tools for assessing cognitive impairment in the early stages of Alzheimer's disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer's Association convened a meeting to discuss state of the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real-world situations in order to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.

NIA outreach to minority and health disparity populations can a toolbox for recruitment and retention be far behind?

The ability to locate the right research tool at the right time for recruitment and retention of minority and health disparity populations is a challenge. This article provides an introduction to a number of recruitment and retention tools in a National Institute on Aging Health Disparities Toolbox and to this special edition on challenges and opportunities in recruitment and retention of minority populations in Alzheimer disease and dementia research. The Health Disparities Toolbox and Health Disparities Resource Persons Network are described along with other more established resource tools including the Alzheimer Disease Center Education Cores, Alzheimer Disease Education and Referral Center, and Resource Centers for Minority Aging Research. Nine featured articles are introduced. The articles address a range of concerns including what we know and do not know, conceptual and theoretical perspectives framing issues of diversity and inclusion, success as a result of sustained investment of time and community partnerships, the significant issue of mistrust, willingness to participate in research as a dynamic personal attribute, Helpline Service and the amount of resources required for success, assistance in working with Limited English Proficiency elders, and sage advice from social marketing and investigations of health literacy as a barrier to recruitment and retention. Finally, an appeal is made for scientists to share tools for the National Institute on Aging Health Disparity Toolbox and to join the Health Disparities Resource Persons Network.

No evidence for cognitive dysfunction or depression in patients with mild restless legs syndrome.

Restless legs syndrome is a common disorder that may interrupt sleep and has been reported to produce daytime fatigue and/or mood changes. This study assessed whether patients with RLS have more cognitive dysfunction and depression than individuals of the same age and education who do not have RLS. The study showed that older individuals with mild RLS for at least 1 year do not have cognitive dysfunction and are not depressed compared with a control group of similar age and education.

Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer's disease.

BACKGROUND: We evaluated the amounts of amyloid beta (Abeta)) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Abeta plasma levels and Alzheimer's disease (AD) pathology. METHODS: Amyloid beta levels were measured in (1) the plasma of AD and nondemented (ND) controls in a longitudinal study, (2) the plasma of a cohort of AD patients receiving a cholinesterase inhibitor, and (3) the skeletal muscle, liver, aorta, platelets, leptomeningeal arteries, and in gray and white matter of AD and ND control subjects. RESULTS: Plasma Abeta levels fluctuated over time and among individuals, suggesting continuous contributions from brain and peripheral tissues and associations with reactive circulating proteins. Arteries with atherosclerosis had larger amounts of Abeta40 than disease-free vessels. Inactivated platelets contained more Abeta peptides than activated ones. Substantially more Abeta was present in liver samples from ND patients. Overall, AD brain and skeletal muscle contained increased levels of Abeta. CONCLUSIONS: Efforts to use plasma levels of Abeta peptides as AD biomarkers or disease-staging scales have failed. Peripheral tissues might contribute to both the circulating amyloid pool and AD pathology within the brain and its vasculature. The wide spread of plasma Abeta values is also due in part to the ability of Abeta to bind to a variety of plasma and membrane proteins. Sources outside the CNS must be accounted for because pharmacologic interventions to reduce cerebral amyloid are assessed by monitoring Abeta plasma levels. Furthermore, the long-range impact of Abeta immunotherapy on peripheral Abeta sources should also be considered.

Challenges to the recognition and assessment of Alzheimer's disease in American Indians of the southwestern United States.

Little is known about Alzheimer's disease (AD) and related neurodegenerative diseases in American Indian (AI) populations. To provide appropriate health care to elder AIs, whose population is expected to increase dramatically during the next 50 years, it is imperative to attain a better understanding of the interaction of culture and disease in this underserved population. Raising awareness in the AI population regarding the nature of dementia as it compares to normal aging and the development of culturally appropriate instruments to detect and stage AD are essential for future health care efforts. Barriers restricting clinical service to this population include historical factors relating to access to health care, cultural beliefs regarding aging, demographic diversity of the population, competing epidemiologic risk factors, and lack of proper assessment tools for clinicians.

Studies on the effect of the apolipoprotein E genotype on the lipid profile in Alzheimer's disease.

OBJECTIVE: To determine whether Apolipoprotein E4 (Apo E4) gene status or ApoE gene dose affect the lipid profile in AD. BACKGROUND: Links between hypercholesterolemia and AD development continue to grow. Presently, limited information exists about the influence of the Apo E genotype on the lipid profile characteristics in AD. METHODS: We examined the lipid profiles (total cholesterol (TC), high-density lipoprotein (HDL), lower-density lipoprotein (LDL), TC/HDL ratio, and triglyceride (TG) levels) of 142 subjects with probable or possible AD (mean age 76.5 +/- 8.9 years), not on lipid lowering therapy by Apo E genotype. Assessment was done by gene status and gene dose. RESULTS: ApoE4 gene status did not reveal any significant differences in the lipid profile except for LDL. However, significant differences were observed by ApoE gene dose. CONCLUSION: ApoE gene status has minimal influence on the lipid panel or mean age in AD. Apo E gene dose does influence the lipid panel with Apo E 2/2, and 2/3 having significantly better lipid panels and older age of onset.