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

Measures of Resting State EEG Rhythms for Clinical Trials in Alzheimer’s Disease:Recommendations of an Expert Panel

The Electrophysiology Professional Interest Area (EPIA) and Global Brain Consortium endorsed recommendations on candidate electroencephalography (EEG) measures for Alzheimer's disease (AD) clinical trials. The Panel reviewed the field literature. As most consistent findings, AD patients with mild cognitive impairment and dementia showed abnormalities in peak frequency, power, and "interrelatedness" at posterior alpha (8-12Hz) and widespread delta (<4Hz) and theta (4-8Hz) rhythms in relation to disease progression and interventions. The following consensus statements were subscribed: (1) Standardization of instructions to patients, resting state EEG (rsEEG) recording methods, and selection of artifact-free rsEEG periods are needed; (2) power density and "interrelatedness" rsEEG measures (e.g., directed transfer function, phase lag index, linear lagged connectivity, etc.) at delta, theta, and alpha frequency bands may be use for stratification of AD patients and monitoring of disease progression and intervention; and (3) international multisectoral initiatives are mandatory for regulatory purposes

The impact of SARS-CoV-2 in dementia across Latin America : A call for an urgent regional plan and coordinated response

The SARS-CoV-2 global pandemic will disproportionately impact countries with weak economies and vulnerable populations including people with dementia. Latin American and Caribbean countries (LACs) are burdened with unstable economic development, fragile health systems, massive economic disparities, and a high prevalence of dementia. Here, we underscore the selective impact of SARS-CoV-2 on dementia among LACs, the specific strain on health systems devoted to dementia, and the subsequent effect of increasing inequalities among those with dementia in the region. Implementation of best practices for mitigation and containment faces particularly steep challenges in LACs. Based upon our consideration of these issues, we urgently call for a coordinated action plan, including the development of inexpensive mass testing and multilevel regional coordination for dementia care and related actions. Brain health diplomacy should lead to a shared and escalated response across the region, coordinating leadership, and triangulation between governments and international multilateral networks

Dementia in Latin America : paving the way towards a regional action plan

Regional challenges faced by Latin American and Caribbean countries (LACs) to fight dementia, such as heterogeneity, diversity, political instabilities, and socioeconomic disparities, can be addressed more effectively grounded in a collaborative setting based on the open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking and translational research) and align them to current global strategies to translate regional knowledge into actions with transformative power. Then, by characterizing genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions and mapping these to the above challenges, we provide the basic mosaics of knowledge that will pave the way towards a KtAF. We describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF

Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

A virtual environment for the assessment and the rehabilitation of the visuo-constructional ability in dementia patients

This study proposes a VE that offers a reliable diagnosis of the stage of cognitive decline in dementia patients and assists the delay of this decline in terms of the visuo-constructional ability. The proposed VE, in the case of the assessment, presents a visuo-constructional completion task, which requires spatial perception, motor memory and the perception of the target object. In the case of the rehabilitation the VE uses sound as audio-feedback that, with the aid of the music perception, tends to develop an enhancement in the visuo-construction ability of the dementia patients that can be generalized even outside of the VE. The study examined 30 subjects that were normal controls (N), 30 patients suffering from memory disorders (Age-Associated Memory Impairment--AAMI) and 30 suffering from Alzheimer's Disease (AD). The results showed that there is a significant correlation between the performance in the visuo-constructional task and the dementia diagnosis. It also seems that the visuo-constructional ability of the (AD) patients can be statistically improved by the audio experience in the VE. The empirical results of this study offer an alternative diagnosis and treatment of dementia patients and could share some light in the brain sub-systems that are responsible for the visuo-constructional ability. Further studies are required in order to investigate the nature of this phenomenon more

Making pre-screening for Alzheimer's disease (AD) and Postoperative delirium among post-acute COVID-19 syndrome - (PACS) a national priority: The Deep Neuro Study [version 1; peer review: 2 approved, 1 approved with reservations]

SARS-CoV-2 effects on cognition is a vibrant area of active research. Many researchers suggest that COVID-19 patients with severe symptoms leading to hospitalization, sustain significant neurodegenerative injury, such as encephalopathy and poor discharge disposition. However, despite some post-acute COVID-19 syndrome (PACS) case series that have described elevated neurodegenerative biomarkers, no studies have been identified that directly compared levels to those in mild cognitive impairment, non-PACS postoperative delirium patients after major non-emergent surgery or preclinical Alzheimer’s Disease (AD) patients, that have clinical evidence of Alzheimer's without symptoms. According to recent estimates, there may be 416 million people globally on the AD continuum, which include approximately 315 million people with preclinical AD. In light of all the above, a more effective application of digital biomarker and explainable artificial intelligence methodologies that explored amyloid beta, neuronal, axonal, and glial markers in relation to neurological complications in-hospital or later outcomes could significantly assist progress in the field. Easy and scalable subjects’ risk stratification is of utmost importance, yet current international collaboration initiatives are still challenging due to the limited explainability and accuracy to identify individuals at risk or in the earliest stages that might be candidates for future clinical trials. In this open letter, we propose the administration of selected digital biomarkers previously discovered and validated in other EU funded studies to become a routine assessment for non-PACS preoperative cognitive impairment, PACS neurological complications in-hospital or later PACS and non-PACS improvement in cognition after surgery. The open letter also includes an economic analysis of the implications for such national level initiatives. Similar collaboration initiatives could have existing prediagnostic detection and progression prediction solutions pre-screen the stage before and around diagnosis, enabling new disease manifestation mapping and pushing the field into unchartered territory

Comparative neurophysiological study of early screening methods for Alzheimer disease

The purpose of this thesis was to compare and correlate: a)a novel virtual reality environment, which was designed to assess everyday basic and complex activities, e.g. spatial navigation during a visit to a virtual museum or a virtual fire evacuation procedure under time pressure, with b) standard neuropsychological questionnaires and also neurophysiological measures such as c) the magnetic reasonance imaging (MRI) or the d) EEG and the Εvent Related Potentials (ERPs). The aim was to investigate the use of the individualized performance profiles, from the virtual reality environments above, as a screening tool for early dementia. According to the literature, there has been only one previous work with virtual reality and its use as an early screening tool for MCI but there is no study that compares its usefulness in comparison with ERPs, EEGs or MRIs. This study is a monographic dissertation that reports on three stages for the evaluation studies, which were published, investigating the use of virtual realities as an early screening instrument for early dementia using similar methodological approaches. According to the results of our longitudinal studies about the sensitivity and specificity of the methods above for the early screening of MCI progressing to AD, we found that the virtual reality performance profiles had a 94% sensitivity and 82% specificity for the early detection of MCI progressors, followed by ERPs with 88% sensitivity and 78% specificity. The MRI had 83% sensitivity and 75% specificity with the neuropsychological having 78% sensitivity and 63% specificity in general. In conclusion the virtual reality realistic performance profiles proved to the have the higher sensitivity and specificity scores followed closely by the ERPs. In this context this study results of previous studies about the usefulness of P3b latencies at the parietal site as a tool for accessing decline progression but also as an AD-converter predictor. These results generally show that early changes in the performance score in virtual reality may reflect deficits of attention process linked to the functional memory and impairment of the frontal treatment in patients with MCI and for patients who are in the early stage of AD In conclusion, the unique contribution of this thesis work is to develop and empirical study of an innovative virtual reality environment, which was less structured and which looked more like a real daily missions than the existing questionnaires, laboratory neurophysiological measurements. This research has shown that virtual reality tests of daily operations may be better predictors of behavior of the real world than many of the commonly used traditional tests of executive functions. The virtual reality system used herein is portable and can be used to simulate various environments and various navigation requirements (cognitive, motor, visual), easily allowing the creation of an ecologically valid study and testing in a variety of clinical and research settings.Ο σκοπός της παρούσας διατριβής ήταν η σύγκριση και συσχέτιση α) ενός καινοτόμου περιβάλλοντος εικονικής πραγματικότητας, το οποίο σχεδιάστηκε για την αξιολόγηση βασικών και σύνθετων καθημερινών δραστηριοτήτων, π.χ., πλοήγηση στο χώρο κατά τη διάρκεια μιας επίσκεψης σε ένα εικονικό μουσείο ή μιας εικονικής διαδικασίας εκκένωσης λόγω πυρκαγιάς υπό πίεση χρόνου, με β) τυποποιημένα νευροψυχολογικά ερωτηματολόγια, γ) νευροφυσιολογικές μετρήσεις, όπως είναι το ΗΕΓ και τα ακουστικά γνωσιακά προκλητά δυναμικά (ΑΓΠΔ) και δ) νευροαπεικόνιση όπως είναι η μαγνητική τομογραφία. Απώτερος στόχος ήταν η διερεύνηση της χρήσης των εξατομικευμένων αποτελεσμάτων απόδοσης, από τα ανωτέρω περιβάλλοντα εικονικής πραγματικότητας, ως εργαλείο ανίχνευσης για την πρώιμη άνοια. Σύμφωνα με τη βιβλιογραφία, υπήρξε μόνο ένα προηγούμενο έργο με εικονική πραγματικότητα και τη χρήση της ως εργαλείο πρώιμης ανίχνευσης για την ΗΝΔ, αλλά δεν υπάρχει καμία μελέτη που να συγκρίνει τη χρησιμότητά της σε σχέση με σύγχρονους μη παρεμβατικούς βιοδείκτες όπως είναι τα προκλητά δυναμικά, το ΗΕΓ και η μαγνητική τομογραφία. Η παρούσα εργασία είναι μια μονογραφία η οποία αναφέρεται σε τρία στάδια, τμήματα των οποίων δημοσιεύτηκαν, οι οποίες διερεύνησαν τη χρήση εικονικών πραγματικοτήτων ως εργαλείο πρώιμης ανίχνευσης για την πρώιμη άνοια με χρήση διαφόρων μεθοδολογικών προσεγγίσεων. Σύμφωνα με τα αποτελέσματα των διαχρονικών αυτών μελετών σχετικά με την ευαισθησία και εξειδίκευση καθεμίας από τις παραπάνω μεθόδους για την πρώιμη ανίχνευση της ΗΝΔ, οι επιδόσεις στη δοκιμασία εικονικής πραγματικότητας και τα ΑΓΠΔ μπόρεσαν να διακρίνουν την ομάδα ΗΝΔ που προχώρησε σε ΝΑ με 94% ευαισθησία, 82% εξειδίκευση, και 88% ευαισθησία, 78% εξειδίκευση, αντίστοιχα. Η νευροαπεικόνιση και οι νευροψυχολογικές δοκιμασίες, έδειξαν 83% ευαισθησία, 75% εξειδίκευση και 78% ευαισθησία, 63% εξειδίκευση, αντίστοιχα. Συμπερασματικά, το περιβάλλον εικονικής πραγματικότητας έδειξε τη μεγαλύτερη ευαισθησία και εξειδίκευση στην πρώιμη ανίχνευση της ΗΝΔ, με τα ΑΓΠΔ να ακολουθούν με λίγο λιγότερη ευαισθησία και εξειδίκευση. Σε αυτό το πλαίσιο, η παρούσα εργασία επιβεβαίωσε επίσης τα αποτελέσματα προηγούμενων μελετών για τη χρησιμότητα των λανθανόντων χρόνων των προκλητών δυναμικών στη βρεγματική περιοχή ως εργαλείο για την εκτίμηση της εξέλιξης της έκπτωσης αλλά και ως παράγοντας πρόβλεψης της εξέλιξης σε ΝΑ. Τα αποτελέσματα αυτά δείχνουν γενικά ότι οι πρώιμες αλλαγές της βαθμολογίας επίδοσης στην εικονική πραγματικότητα μπορεί να αντικατοπτρίζουν το έλλειμμα της διαδικασίας προσοχής που συνδέεται με τη λειτουργική μνήμη και τη δυσλειτουργία της μετωπιαίας επεξεργασίας σε ασθενείς με ΗΝΔ και για ασθενείς που βρίσκονται στο πρώιμο στάδιο της ΝΑ. Εν κατακλείδι, η συμβολή της παρούσας εργασίας έγκειται στην ανάπτυξη και εμπειρική μελέτη ενός καινοτόμου περιβάλλοντος εικονικής πραγματικότητας, το οποίο ήταν λιγότερο δομημένο και το οποίο έμοιαζε περισσότερο με πραγματικές καθημερινές αποστολές από ό,τι τα υφιστάμενα ερωτηματολόγια ή οι εργαστηριακές νευροφυσιολογικές μετρήσεις. Η παρούσα έρευνα απέδειξε ότι οι δοκιμασίες εικονικής πραγματικότητας των καθημερινών λειτουργιών μπορεί να είναι καλύτεροι παράγοντες πρόβλεψης των συμπεριφορών του πραγματικού κόσμου από ότι πολλές από τις συχνότερα χρησιμοποιούμενες παραδοσιακές δοκιμασίες των επιτελικών λειτουργιών. Το σύστημα εικονικής πραγματικότητας που χρησιμοποιείται εδώ είναι φορητό και μπορεί να χρησιμοποιηθεί για προσομοίωση διαφόρων περιβαλλόντων και διαφόρων απαιτήσεων πλοήγησης (νοητικών, κινητικών, οπτικών), επιτρέποντας εύκολα τη δημιουργία μιας οικολογικά έγκυρης μελέτης και ελέγχου σε ποικίλα κλινικά και ερευνητικά περιβάλλοντα