Description of the Method for Evaluating Digital Endpoints in Alzheimer Disease Study : Protocol for an Exploratory, Cross-sectional Study

©Jelena Curcic, Vanessa Vallejo, Jennifer Sorinas, Oleksandr Sverdlov, Jens Praestgaard, Mateusz Piksa, Mark Deurinck, Gul Erdemli, Maximilian Bügler, Ioannis Tarnanas, Nick Taptiklis, Francesca Cormack, Rebekka Anker, Fabien Massé, William Souillard-Mandar, Nathan Intrator, Lior Molcho, Erica Madero, Nicholas Bott, Mieko Chambers, Josef Tamory, Matias Shulz, Gerardo Fernandez, William Simpson, Jessica Robin, Jón G Snædal, Jang-Ho Cha, Kristin Hannesdottir. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 10.08.2022.BACKGROUND: More sensitive and less burdensome efficacy end points are urgently needed to improve the effectiveness of clinical drug development for Alzheimer disease (AD). Although conventional end points lack sensitivity, digital technologies hold promise for amplifying the detection of treatment signals and capturing cognitive anomalies at earlier disease stages. Using digital technologies and combining several test modalities allow for the collection of richer information about cognitive and functional status, which is not ascertainable via conventional paper-and-pencil tests. OBJECTIVE: This study aimed to assess the psychometric properties, operational feasibility, and patient acceptance of 10 promising technologies that are to be used as efficacy end points to measure cognition in future clinical drug trials. METHODS: The Method for Evaluating Digital Endpoints in Alzheimer Disease study is an exploratory, cross-sectional, noninterventional study that will evaluate 10 digital technologies' ability to accurately classify participants into 4 cohorts according to the severity of cognitive impairment and dementia. Moreover, this study will assess the psychometric properties of each of the tested digital technologies, including the acceptable range to assess ceiling and floor effects, concurrent validity to correlate digital outcome measures to traditional paper-and-pencil tests in AD, reliability to compare test and retest, and responsiveness to evaluate the sensitivity to change in a mild cognitive challenge model. This study included 50 eligible male and female participants (aged between 60 and 80 years), of whom 13 (26%) were amyloid-negative, cognitively healthy participants (controls); 12 (24%) were amyloid-positive, cognitively healthy participants (presymptomatic); 13 (26%) had mild cognitive impairment (predementia); and 12 (24%) had mild AD (mild dementia). This study involved 4 in-clinic visits. During the initial visit, all participants completed all conventional paper-and-pencil assessments. During the following 3 visits, the participants underwent a series of novel digital assessments. RESULTS: Participant recruitment and data collection began in June 2020 and continued until June 2021. Hence, the data collection occurred during the COVID-19 pandemic (SARS-CoV-2 virus pandemic). Data were successfully collected from all digital technologies to evaluate statistical and operational performance and patient acceptance. This paper reports the baseline demographics and characteristics of the population studied as well as the study's progress during the pandemic. CONCLUSIONS: This study was designed to generate feasibility insights and validation data to help advance novel digital technologies in clinical drug development. The learnings from this study will help guide future methods for assessing novel digital technologies and inform clinical drug trials in early AD, aiming to enhance clinical end point strategies with digital technologies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35442.Peer reviewe

A study of the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) in an Icelandic elderly population

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenThe Alzheimer's Disease Assessment Scale (ADAS) is designed for screening of cognitive and non-cognitive dysfunctions characteristic of persons with probable Alzheimer's disease (AD). The cognitive part of the scale (ADAS-Cog) is both convenient for screening of probable AD and as a measure of cognitive functioning during drug intervention. The aim of this study was to translate the ADAS-Cognitive sub-test (ADAS-Cog) into Icelandic and to study its application in an elderly Icelandic population. The Mini-Mental State Examination (MMSE) and the ADAS-Cog were administered to 20 AD patients and 20 controls. Each patient was also rated on the Global Deterioration Scale (GDS). The probable AD patients were divided into two groups based on their GDS: 3-4 and 5-6 points. The patients were also divided into two groups based on their MMSE score: very mild to mild (23-30 points) and mild to moderate (15-22 points). Furthermore, the subjects were divided into two age groups: 65-76 and 77-92 years. Results revealed a highly significant difference on MMSE (22.3 +/- 3.4; 26.8 +/- 1.6; P < 0.05) and ADAS-Cog (18.4 +/- 7.7; 7.3 +/- 3.5; P < 0.05) scores for patients and controls respectively. AD patients also performed significantly worse than the elderly control group on eight of the 11 sub-tests. Thus, the present findings are mainly in line with those of previous studies. The scale exceeds other screening tests such as the MMSE in that it addresses in more detail the symptoms of AD and is valuable for early detection of the illness and staging. ADAS-Cog plays an important role in the diagnostic makeup of AD along with other detailed investigations, such as neuropsychological assessment

The ambivalence towards neuropsychology in dementia research, diagnosis, and drug development: Myths and misconceptions.

Clinical assessments remain the gold standard for diagnosing neurodegenerative dementia and monitoring disease progression and treatment effects as well research. However, rapid soluble biomarker developments hold promise for increasingly targeted therapeutic approaches, targeted selection of participants in clinical trials, and more direct physiological efficacy readouts. Unfortunately, the anchoring of biomarker research to clinical symptomatology and disease progression is often based on brief and uninformative cognitive tests or screening tools that lack sensitivity to the early stages of cognitive decline. The use of these tools has given the impression that cognitive symptoms occur relatively late in the disease and that disease progression in the early stages of disease is slow. This can hinder advancements in the field and may lead to treatment interventions occurring too late. Poor cognitive test selection has likely been a factor in the failure record of dementia drug development over the last two decades. A thorough cognitive assessment is a powerful tool in the hands of an expert neuropsychologist and continues to play a key role in the accurate and early diagnosis of neurodegenerative disease. This clinical assessment is very different from the cognitive testing we traditionally see in dementia biomarker research and drug development. Yet the distinction between the two approaches is unclear to many. This paper aims to elucidate some of the myths and misconceptions around cognitive research in dementia and suggests a way forward to facilitate biomarker and drug development through the improved utility of cognitive assessment tools

Digital Therapeutics—An Integral Component of Digital Innovation in Drug Development

Digital therapeutics represent a new treatment modality in which digital systems such as smartphone apps are used as regulatory-approved, prescribed therapeutic interventions to treat medical conditions. In this paper, we provide a critical overview of the rationale for investing into such novel modalities, including the unmet medical needs addressed by digital therapeutics and the potential for reducing current costs of medical care. We also discuss emerging pathways to regulatory approval and how innovative business models are enabling further growth in the development of digital therapeutics. We conclude by providing some recent examples of digital therapeutics that have gained regulatory approval and highlight opportunities for the near future

Validation of the Icelandic version of the Neuropsychiatric Inventory with Caregiver Distress (NPI-D).

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.Background: Dementia is a complex and often debilitating illness, presenting with not only wide-ranging cognitive impairment but also neuropsychiatric challenges, which can have diverse consequences in quality of life for both patient and caregiver. Aim: Studying the validity and reliability of an Icelandic translation of the Neuropsychiatric Inventory with Caregiver Distress (NPI-D). Methods: NPI-D was administered to 38 primary caregivers of dementia patients. The concurrent validity was explored by statistically comparing the NPI-D to the Behavioural Pathology in Alzheimer ’ s Disease Rating Scale (BEHAVE-AD) and the Geriatric Depression Scale (GDS). Regarding caregiver distress, concurrent validity was established between NPI-D, BEHAVE-AD Global Rating and two other caregiver distress scales. Results: Signifi cant correlation was found when total score on the BEHAVE-AD was compared with total score on the NPI-D. All NPI-D subscales achieved signifi cant correlation with the corresponding BEHAVE-AD subscales apart from the ‘ depression/dysphoria subscale ’ . This NPI-D subscale correlated however, signifi cantly with the GDS depression scale, a frequent and well validated measure of depressive symptoms in the elderly population. Cronbach ’ s alpha coeffi cient indicated a high degree of overall internal consistency among the items of the NPI-D. Interestingly, apathy was the most frequent neuropsychiatric disturbance and the only subscale that differed signifi cantly between dementia severity levels. Finally, when studying caregiver distress, the NPI-D showed good concurrent validity with other measures of caregiver burden and distress. Conclusions: The results demonstrate an acceptable level of validity and reliability; therefore the Icelandic translation of the NPI-D is well suited for identifying neuropsychiatric symptoms in dementia and associated caregiver burden.Landspitali University Hospita

Engineering buildings at Monash University, Clayton, Victoria, architects Bates, Smart and McCutcheon, 1962, [3] [picture] /

Condition: Good.; Title devised by cataloguer based on inscription on reverse.; Part of Wolfgang Sievers photographic archive.; Sievers number: 3236AF.; Also available in an electronic version via the Internet at: http://nla.gov.au/nla.pic-vn4196701

Brief Memory and Executive Test: evaluation of a new screening test for cognitive impairment due to small vessel disease

Background: cerebral small vessel disease (SVD) is the most common cause of vascular cognitive impairment (VCI). Despite this, there is a paucity of rapid simple screening tools to identify cognitive impairment in SVD and differentiate it from other common dementia types. Objective: to validate a new screening test for cognitive impairment in SVD, the Brief Memory and Executive Test (BMET) battery, and examine its ability to detect SVD and differentiate it from Alzheimer's disease (AD). Subjects: 45 patients with SVD, 27 patients with AD and 80 normal controls. Methods: the BMET includes brief tests of executive functioning and processing speed, with comparative tests of memory and orientation. Group discrimination was calculated using discriminant function analysis. Results: the BMET took an average of 10 min to administer. It showed high sensitivity (91%) and specificity (85%) in differentiating SVD patients with cognitive impairment from AD patients. As a comparison the mini-mental state examination had lower sensitivity (63%) and specificity (62%). Conclusions: the BMET is a simple and quick to administer clinical tool for the detection of VCI in SVD and its differentiation from AD impairment. Further multicentre studies are required to evaluate and compare it with other existing screening tests

A study of new exploratory tools, digital technologies and biomarkers to characterize depression

Background: Digital technologies have the potential to provide objective and precise tools to detect depression-related symptoms. Deployment of digital technologies in clinical research can enable collection of large volumes of clinically relevant data that may not be captured using conventional psychometric questionnaires and patient-reported outcomes. Rigorous methodology studies to develop novel digital endpoints in depression are warranted. Objective: We conducted an exploratory, cross-sectional study to assess feasibility of several novel digital technologies in subjects with major depressive disorder (MDD) and normal healthy controls. The study aimed at assessing utility and accuracy of the digital technologies as potential diagnostic tools for MDD, as well as correlating digital biomarkers to clinically validated psychometric questionnaires in depression. Methods: A cross-sectional, non-interventional study of 20 subjects with MDD and 20 normal healthy volunteers was conducted at the Centre for Human Drug Research (CHDR), the Netherlands. Eligible participants attended three in-clinic visits (days 1, 7, and 14), at which they underwent a series of assessments, including conventional clinical psychometric questionnaires and novel digital technologies. Between the visits, there was at-home collection of data through mobile applications. In all, eight digital technologies were evaluated in this study. Results: Our data analysis was organized by technology – to better understand individual features of various technologies. In many cases, we obtained simple, parsimonious models that have reasonably high diagnostic accuracy and potential to predict standard clinical outcome in depression. Conclusion: This study generated many useful insights for future methodology studies of digital technologies and proof of-concept clinical trials in depression and possibly other indications