Digital Tools Abound, Yet Remote Biomarkers for FTD Remain Exploratory

Series - AFTD Holloway Summit 2022: Digital Assessment Tools for FTD:

Part 2 of 2

Frontotemporal dementia is a wildly heterogeneous group of disorders, and many people with an FTD have difficulty getting an accurate diagnosis, let alone proper care or treatment. Digital biomarkers would expand access to services and speed therapy development. In recent years, sophisticated tools have been created that can track everything from movement to sleep patterns, social life, speech features, memory, balance, and beyond. At the inaugural Holloway Summit, held May 18-20 in Miami, leaders across the field of FTD and related disorders came together to discuss what has been developed so far, and how to streamline the technological offerings into standardized, validated digital biomarkers that reliably aid in diagnosis, prognosis, and clinical trials (see Part 1 of this series).

Fit for Purpose
At this point, most digital FTD markers are in the research or validation phase, and are not yet in use in clinical trials. That said, a broad array of digital measures, devices, and apps are being tested by different groups across the world. “How do we best leverage all of these digital technologies to accelerate treatment development?” Adam Boxer of the University of California, San Francisco, asked the audience. He thinks it’s crucial to sort out which markers best fit defined, given purposes, such as diagnosis, prognosis, or tracking treatment effects. It will also be critical to harmonize digital health technologies across observational cohorts.

Together with Jonathan Rohrer at University College, London, Boxer heads the FTD Prevention Initiative, a global collaboration between FTD cohorts. It includes ALLFTD, GENFI, Australia’s Dominantly Inherited Non-Alzheimer Dementias (DINAD) study, New Zealand’s FTD Genetic (FTDGeNZ) study, and South America’s Research Dementia Latin America (ReDLaT) study (Mar 2021 news). Selecting digital markers that can be deployed across cultures will be essential for conducting global research studies and clinical trials in this initiative, particularly in countries where most people lack access to medical centers, Boxer emphasized.

Is there any sign yet of harmonization between the flurry of devices and measures that are in the works? ALLFTD and GENFI are planning a pilot study in which they swap apps, trying out the ALLFTD Mobile app in the GENFI cohort and the Ignite app in the ALLFTD cohort (see Part 1). Boxer wants to do this on a larger international scale in FPI, he told Alzforum, but acknowledged that it took ALLFTD and GENFI years just to integrate their basic data on age at symptom onset and disease duration (Moore et al., 2020). “We have to anticipate this with digital measures,” Boxer said. He emphasized that data needs to be shared broadly to accelerate the advance of digital markers, and yet, agreeing on ways to share complex and sensitive data continues pose significant challenges for the field.

Path to Patients: Learning from Parkinson's
In its quest to streamline digital technologies and measures into a few broadly usable tools, the FTD field can learn from the trials and tribulations in Parkinson's disease, ALS, and Alzheimer's disease. The Holloway Summit featured talks about digital technology development in these disorders, all of which have some overlap with FTD.

Diane Stephenson, who founded the Critical Path for Parkinson’s (CPP) Consortium, told the audience that data sharing on a global scale, involvement of regulatory agencies at every step along the way, and listening seriously to patients are essential if digital health technology development is to succeed. Founded seven years ago, CPP convenes leaders in academia, industry, foundations, regulatory agencies, governmental organizations, and people with PD. CPP has integrated data from more than 15,000 participants in PD research studies and clinical trials. With this data, the consortium is designing PD clinical trials, and looking for biomarkers that can enrich trials with people in the earliest stages of disease. Digital health technologies are chief among the consortium’s goals, Stephenson said.

PD has been the flagship disease for digital tools because, to tech people, tracking movement symptoms with built-in accelerometers seems like a no-brainer. “But PD is not that simple,” Stephenson said. Even in its earliest stages, patients have non-motor symptoms, including restless sleep, pain, fatigue, and changes in mood and cognition, which are rarely included as primary endpoints in clinical trials. To develop digital tools for early PD, CPP formed the industry, academia, and patient advocacy consortium 3DT. It uses an open, precompetitive model to transform digital tools from siloed, exploratory measures into standardized biomarkers that can be put to broad use in clinical trials (Stephenson et al., 2020; Stephenson et al., 2021). 

Take, for example, the Wearable Assessments in the Clinic and Home in PD (WATCH-PD) study. With Biogen and Takeda, along with University of Rochester scientists Ray Dorsey, Jamie Adams and Jennifer Mammen, 3DT compared in-clinic assessments to those taken remotely via a combination of smartwatch and smartphone. Using these wearable devices equipped with motion sensors, microphones for recording speech, as well as participant questionnaires, researchers monitored a range of motor and non-motor symptoms from afar.

Initially, the study was going to include people with early PD who showed signs of dopamine deficiency via DaT scan. However, after consulting with the FDA prior to the start of the study, the investigators added a control group. They also took a hint from a public rejection letter the FDA had posted in response to an application by Verily. That company had developed a digitized version of the MDS-UPDRS Part III, considered the gold standard measure of motor symptoms. The regulators wrote that the digitized MDS-UPDRS Part III “cannot be interpreted as being meaningful to patients.” To avoid the same fate, the WATCH-PD investigators worked with the FDA to devise an extensive exit interview for participants that would help them discern which digital measurements most closely link to aspects that are important in their lives. Stephenson said those interviews are ongoing.

Preliminary findings from the WATCH-PD study are promising, Stephenson reported. For example, by picking up a reduced arm swing, the smartwatch could tell the difference between people with PD and controls. This is a big deal, Stephenson said, because these participants were at such an early stage. It also corroborates previous studies in pathogenic LRRK2 mutation carriers, whose arm swing changed while they were presymptomatic (Mirelman et al., 2016). 

Stephenson said that the WATCH-PD study is an example of how this kind of collaboration can work. Such large collaborative efforts are needed to advance digital health technologies in FTD, as well, she believes.

One new example of an open-science, all-hands-on-deck approach is Everything ALS. Founded in 2020 by Indu Navar, a tech entrepreneur whose husband died from the disease in 2019, EALS is a nonprofit organization featuring a global online platform through which people with ALS can engage in studies. By bringing together patients from around the world, ALS researchers in academia and industry, and tech and device companies, EALS aims to develop digital biomarkers that will support early diagnosis of ALS and make clinical trials more efficient. At the Holloway summit, Navar emphasized that even for people like her husband, who had access to the best medical care, merely obtaining an ALS diagnosis was a long process. After that, the measures used to track his disease progression were subjective and lacking in sensitivity.

Navar formed an international patient network that runs studies on digital tools. Its nearly 5,000 participants take part in studies to try out different digital measures. The measurements and technologies EALS explores include structured and natural speech analysis, video tracking of facial movements, monitored internet search behavior, and measuring subtle differences in the way people use their keyboard mouse.

With the help of artificial intelligence, EALS is amassing a dataset meant to be open to researchers in academia and industry. For example, the EALS speech and facial study, which is hunting for ALS-specific signals in speech and facial gestures, includes 750 participants so far. They have taken part in 6,000 sessions yielding 1,000 hours of data, which is analyzed in partnership with artificial intelligence companies and shared with pharma and academic researchers, Navar reported.

All studies run through the platform are IRB-approved, and participants consent to having their data be shared in de-identified form. They can access their own data, because this type of transparency is essential for keeping people engaged in the study, Navar said.

Path to Biomarkers? Using an online platform and partnering with Microsoft, IBM, modality.ai, pharma companies, and medical centers, EALS boasts a growing community of people with ALS, who are joining studies of potential digital health technologies for diagnosis, prognosis, and clinical trials. [Courtesy of Indu Navar, EALS.]

BYOD or Take the Study's?
Digital biomarker developers wrestle with the question of whether to design tests to work on a participant’s device—“bring your own device” (BYOD)—or to give participants a specialized study device. The advantage of BYOD is self-evident—most people have a smartphone these days, and who wants to carry another? However, developing digital tools that work consistently across different types of smartphone is not trivial, as Jason Hassenstab of Washington University in St. Louis can attest.

At the summit, Hassenstab described his team's challenges in developing a smartphone app for global trials for the growing Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU). Called the Ambulatory Research in Cognition (ARC) app, it enables daily testing of a user’s spatial memory, processing speed, and associative memory in less than three minutes per session (Aug 2018 conference news). Besides ensuring that the tasks work across languages and cultures, Hassenstab grappled with differences in smartphones, of which more than 19,000 models exist worldwide. For one, tap latency—the time it takes for a phone to register a finger tap—varies markedly between phones, especially those with different operating systems. Even among phones with the same operating system, tap latency can change after a routine software upgrade, or if the phone is in power-saving mode, Hassenstab reported. This spurred Hassenstab to shift away from tasks that rely on response time, and focus on correct answers instead (Aug 2019 news).

Researchers also need to consider how smartphone access varies by demographics. Many people who live in rural areas, or those with low socioeconomic status, lack access to a Wi-Fi signal, and Androids are more common globally than pricier Apple iOS phones.

Despite the challenges, the summit's attendees agreed that digital biomarkers and, ultimately, digital endpoints for clinical trials will be necessary to find effective treatments for FTD. To Boxer, such tools are the key to running global clinical trials. His dream? An app that could be downloaded onto any smartphone, with a culturally harmonized, common set of endpoints. “The technology exists, and I’m naively optimistic that we can make it happen,” Boxer said.—Jessica Shugart

Comments

  1. This was a truly remarkable conference with distinguished experts and diverse stakeholders, all inspired by the Holloway story. I was honored to share our journey in our Critical Path for Parkinson's (CPP) consortium as a case example. I want to be sure to acknowledge the leadership of Ray Dorsey, Jamie Adams, and Jennifer Mammen from University of Rochester, who are the Principal Investigators of the WATCH-PD study. The study has been carried out by the Parkinson's Study Group. We hope that our example illustrates the successful collaboration of all stakeholders including academic experts, industry, regulatory agencies, patient advocacy groups, and people living with Parkinson's.

    View all comments by Diane Stephenson

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References

News Citations

  1. Digital Biomarkers of FTD: How to Move from Tech Tinkering to Trials?
  2. Cohorts Band Together to Get Global FTD Trials Going
  3. Weeklong Chinese Challenge Reveals Subtle Memory Problems
  4. Technology Brings Dementia Detection to the Home

Paper Citations

  1. Moore KM, Nicholas J, Grossman M, McMillan CT, Irwin DJ, Massimo L, Van Deerlin VM, Warren JD, Fox NC, Rossor MN, Mead S, Bocchetta M, Boeve BF, Knopman DS, Graff-Radford NR, Forsberg LK, Rademakers R, Wszolek ZK, van Swieten JC, Jiskoot LC, Meeter LH, Dopper EG, Papma JM, Snowden JS, Saxon J, Jones M, Pickering-Brown S, Le Ber I, Camuzat A, Brice A, Caroppo P, Ghidoni R, Pievani M, Benussi L, Binetti G, Dickerson BC, Lucente D, Krivensky S, Graff C, Öijerstedt L, Fallström M, Thonberg H, Ghoshal N, Morris JC, Borroni B, Benussi A, Padovani A, Galimberti D, Scarpini E, Fumagalli GG, Mackenzie IR, Hsiung GR, Sengdy P, Boxer AL, Rosen H, Taylor JB, Synofzik M, Wilke C, Sulzer P, Hodges JR, Halliday G, Kwok J, Sanchez-Valle R, Lladó A, Borrego-Ecija S, Santana I, Almeida MR, Tábuas-Pereira M, Moreno F, Barandiaran M, Indakoetxea B, Levin J, Danek A, Rowe JB, Cope TE, Otto M, Anderl-Straub S, de Mendonça A, Maruta C, Masellis M, Black SE, Couratier P, Lautrette G, Huey ED, Sorbi S, Nacmias B, Laforce R Jr, Tremblay ML, Vandenberghe R, Damme PV, Rogalski EJ, Weintraub S, Gerhard A, Onyike CU, Ducharme S, Papageorgiou SG, Ng AS, Brodtmann A, Finger E, Guerreiro R, Bras J, Rohrer JD, FTD Prevention Initiative. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. Lancet Neurol. 2020 Feb;19(2):145-156. Epub 2019 Dec 3 PubMed.
  2. Stephenson D, Alexander R, Aggarwal V, Badawy R, Bain L, Bhatnagar R, Bloem BR, Boroojerdi B, Burton J, Cedarbaum JM, Cosman J, Dexter DT, Dockendorf M, Dorsey ER, Dowling AV, Evers LJ, Fisher K, Frasier M, Garcia-Gancedo L, Goldsack JC, Hill D, Hitchcock J, Hu MT, Lawton MP, Lee SJ, Lindemann M, Marek K, Mehrotra N, Meinders MJ, Minchik M, Oliva L, Romero K, Roussos G, Rubens R, Sadar S, Scheeren J, Sengoku E, Simuni T, Stebbins G, Taylor KI, Yang B, Zach N. Precompetitive Consensus Building to Facilitate the Use of Digital Health Technologies to Support Parkinson Disease Drug Development through Regulatory Science. Digit Biomark. 2020;4(Suppl 1):28-49. Epub 2020 Nov 26 PubMed.
  3. Stephenson D, Badawy R, Mathur S, Tome M, Rochester L. Digital Progression Biomarkers as Novel Endpoints in Clinical Trials: A Multistakeholder Perspective. J Parkinsons Dis. 2021;11(s1):S103-S109. PubMed.
  4. Mirelman A, Bernad-Elazari H, Thaler A, Giladi-Yacobi E, Gurevich T, Gana-Weisz M, Saunders-Pullman R, Raymond D, Doan N, Bressman SB, Marder KS, Alcalay RN, Rao AK, Berg D, Brockmann K, Aasly J, Waro BJ, Tolosa E, Vilas D, Pont-Sunyer C, Orr-Urtreger A, Hausdorff JM, Giladi N. Arm swing as a potential new prodromal marker of Parkinson's disease. Mov Disord. 2016 Oct;31(10):1527-1534. PubMed.

External Citations

  1. 3DT
  2. Everything ALS

Further Reading

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