Digital endpoints in clinical trials of Alzheimer's disease and other neurodegenerative diseases: challenges and opportunities.

Alzheimer's disease (AD) and other neurodegenerative diseases such as Parkinson's disease (PD) and Huntington's disease (HD) are associated with progressive cognitive, motor, affective and consequently functional decline considerably affecting Activities of Daily Living (ADL) and quality of life. Standard assessments, such as questionnaires and interviews, cognitive testing, and mobility assessments, lack sensitivity, especially in early stages of neurodegenerative diseases and in the disease progression, and have therefore a limited utility as outcome measurements in clinical trials. Major advances in the last decade in digital technologies have opened a window of opportunity to introduce digital endpoints into clinical trials that can reform the assessment and tracking of neurodegenerative symptoms. The Innovative Health Initiative (IMI)-funded projects RADAR-AD (Remote assessment of disease and relapse-Alzheimer's disease), IDEA-FAST (Identifying digital endpoints to assess fatigue, sleep and ADL in neurodegenerative disorders and immune-mediated inflammatory diseases) and Mobilise-D (Connecting digital mobility assessment to clinical outcomes for regulatory and clinical endorsement) aim to identify digital endpoints relevant for neurodegenerative diseases that provide reliable, objective, and sensitive evaluation of disability and health-related quality of life. In this article, we will draw from the findings and experiences of the different IMI projects in discussing (1) the value of remote technologies to assess neurodegenerative diseases; (2) feasibility, acceptability and usability of digital assessments; (3) challenges related to the use of digital tools; (4) public involvement and the implementation of patient advisory boards; (5) regulatory learnings; and (6) the significance of inter-project exchange and data- and algorithm-sharing

Digital endpoints in clinical trials of Alzheimer’s disease and other neurodegenerative diseases: challenges and opportunities

Alzheimer’s disease (AD) and other neurodegenerative diseases such as Parkinson’s disease (PD) and Huntington’s disease (HD) are associated with progressive cognitive, motor, affective and consequently functional decline considerably affecting Activities of Daily Living (ADL) and quality of life. Standard assessments, such as questionnaires and interviews, cognitive testing, and mobility assessments, lack sensitivity, especially in early stages of neurodegenerative diseases and in the disease progression, and have therefore a limited utility as outcome measurements in clinical trials. Major advances in the last decade in digital technologies have opened a window of opportunity to introduce digital endpoints into clinical trials that can reform the assessment and tracking of neurodegenerative symptoms. The Innovative Health Initiative (IMI)-funded projects RADAR-AD (Remote assessment of disease and relapse—Alzheimer’s disease), IDEA-FAST (Identifying digital endpoints to assess fatigue, sleep and ADL in neurodegenerative disorders and immune-mediated inflammatory diseases) and Mobilise-D (Connecting digital mobility assessment to clinical outcomes for regulatory and clinical endorsement) aim to identify digital endpoints relevant for neurodegenerative diseases that provide reliable, objective, and sensitive evaluation of disability and health-related quality of life. In this article, we will draw from the findings and experiences of the different IMI projects in discussing (1) the value of remote technologies to assess neurodegenerative diseases; (2) feasibility, acceptability and usability of digital assessments; (3) challenges related to the use of digital tools; (4) public involvement and the implementation of patient advisory boards; (5) regulatory learnings; and (6) the significance of inter-project exchange and data- and algorithm-sharing

INVESTIGATING THE STRUCTURAL DYNAMICS OF HUMAN GALECTIN-4 USING SMALL ANGLE X-RAY SCATTERING

Human galectin-4 (hGal4) is a member of the galectin family of proteins with a variety of cellular functions including cell cycle regulation, immunological functions and cell migration. hGal4 is found in the human alimentary tract and has also been implicated in a variety of cancers and inflammatory bowel disease. For this reason, hGal4 has been proposed as a potential drug target or marker for cancer diagnoses. However structural information of the full-length protein is lacking. hGal4 belongs to the tandem-repeat type subfamily of galectins, characterized by two distinct carbohydrate recognition domains within a single peptide chain. The two domains have a conserved amino acid signature shared by all galectins and are linked by a flexible peptide chain. This flexibility has rendered hGal4 difficult to study by traditional structural methods. In the current study, I investigate the structural dynamics of hGal4 using small angle x-ray scattering (SAXS). Using both oscillating-flow cell SAXS and in-line size exclusion chromatography SAXS, I investigated the conformational changes of hGal4 in solution as a function of lactose. This data allowed us to determine the radius of gyration (R$_{g}$) and maximum interparticle distance (D$_{max}$). Furthermore, the SAXS data collected were used to generate ab-initio shape reconstructions for hGal4 both with and without lactose using dummy residue modeling and rigid-body ensemble modeling. My results demonstrate that the flexible peptide linker between the two carbohydrate recognition domains of hGal4 confers conformational flexibility that allows the protein to bind to carbohydrate ligands in an extended conformation and bring together the two domains into a compact structure

Recommendations to address key recruitment challenges of Alzheimers disease clinical trials.

Clinical trials for Alzheimers disease (AD) are slower to enroll study participants, take longer to complete, and are more expensive than trials in most other therapeutic areas. The recruitment and retention of a large number of qualified, diverse volunteers to participate in clinical research studies remain among the key barriers to the successful completion of AD clinical trials. An advisory panel of experts from academia, patient-advocacy organizations, philanthropy, non-profit, government, and industry convened in 2020 to assess the critical challenges facing recruitment in Alzheimers clinical trials and develop a set of recommendations to overcome them. This paper briefly reviews existing challenges in AD clinical research and discusses the feasibility and implications of the panels recommendations for actionable and inclusive solutions to accelerate the development of novel therapies for AD