ALLFTD Mobile App Provides Reliable, Scalable Solution for Remote Evaluations of Frontotemporal Lobar Degeneration

Adam Staffaroni, PhD

A recently published study in JAMA Network Open highlighted the potential for remotely deployed smartphone-based assessments to be used for evaluating and detecting frontotemporal lobar degeneration (FTLD). All told, the use of the ALLFTD mobile app (ALLFTD-mApp) demonstrated moderate to excellent reliability compared with criterion standard measures and brain volumes, and were more sensitive to the earliest stages of familial FTLD than standard neuropsychological tests.¹

In this cohort study of 360 patients, controls and participants with FTLD performed smartphone app-based executive functioning tasks and associative memory task 3 times over 2 weeks. In terms of reliability of the app, except for go/no-go, internal consistency estimates ranged from good to excellent (Cronbach a range, 0.84 [95% CI, 0.81-0.87] to 0.99 [95% CI, 0.99-0.99]) and test-retest reliabilities were moderate to excellent (interclass correlation coefficient [ICC] range, 0.77 [95% CI, 0.69-0.83] to 0.95 [95% CI, 0.93-0.96]) with slightly higher estimates in participants with prodromal or symptomatic FTLD.

Led by Adam Staffaroni, PhD, a clinical neuropsychologist and associate professor at the University of California San Francisco Memory and Aging Center, replicability of ALLFTD-mApp was done by dividing the sample into a discovery cohort (n = 258) and a validation cohort (n = 102). The discovery cohort included all participants enrolled until the initial data free (October 1, 2022) while the validation cohort comprised participants enrolled after October 1, 2022, and 18 pilot participants who completed the first session in person with an examiner present during cognitive pretesting.

Among 329 participants with available Clinical Dementia Rating (CDR) plus National Alzheimer’s Coordinating Center (NACC) FTLD scores, 195 (59.3%) were asymptomatic or preclinical, 66 (20.1%) were prodromal, and 68 (20.7%) were symptomatic. On average participants completed 78% of available smartphone measures over a mean of 2.6 (SD, 0.6) sessions. In participants without symptoms, go/no-go reliability of the ALLFTD-mApp was particularly poor (ICC, 0.10; 95% CI, –0.37 to 0.48) and was thus removed from subsequent validation analyses except for the correlation matrix.

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Results showed an area under the curve (AUC) composite to distinguish those without symptoms from those with dementia of 0.93 (95% CI, 0.90-0.96). Compared with the Montreal Cognitive Assessment (AUC, 0.68; 95% CI, 0.59-0.78), a validated tool in several neurodegenerative trials, the app composite performance (AUC, 0.82; 95% CI, 0.76-0.88) more accurately differentiated participants without symptoms and with prodromal FTLD (z of comparison, –2.49; 95% CI, –0.19 to –0.02; P = .01) with similar accuracy to the UDS3-EF (AUC, 0.81; 95% CI, 0.73-0.88).

Carriers of preclinical C9orf72 and GRN pathogenic variants performed significantly worse than noncarrier controls on 3 tests, whereas they did not significantly differ on criterion standard measures. This group, which included 56 participants without symptoms who were older than 45 years, demonstrated inferior performance on flanker (ß = –0.26; 95% CI, –0.46 to –0.05; P = .02), card sort (ß = –0.28; 95% CI, –0.54 to –0.30; P = .03) and 2-back (ß = –0.49; 95% CI, –0.72 to –0.25; P <.001) assessments. Of note, investigators observed higher, nonsignificant scores on the app Memory test in carriers of preclinical MAPT pathogenic variants (ß = 0.21; 95% CI, –0.50 to 0.58; P = .19).

Additional data from a prespecified ROI analysis showed that worse app executive functioning scores were associated with lower frontoparietal and/or subcortical volume (ß range, 0.34 [95% CI, 0.22-0.46] to 0.50 [95% CI, 0.40-0.60]; P <.001 for all) and worse memory scores with smaller hippocampal volume (ß = 0.45; 95% CI, 0.34-0.56; P <.001). Of note, those experiencing distractions unexpectedly performed better (ß = 0.16; 95% CI, 0.05-0.28; P = .005) and those with iPhone operating systems performed better on 2 speeded tasks: flanker (ß = 0.16; 95% CI, 0.07-0.24; P <.001), and go/no-go (ß = 0.16; 95% CI, 0.06-0.26; P = .002).

The study had a few limitations, including that "Validation analyses focused on participants’ initial task exposure. Future studies will explore whether repeated measurements and more sophisticated approaches to composite building (current composite assumes equal weighting of tests) improve reliability and sensitivity, and a normative sample is being collected to better adjust for demographic effects on testing. Longitudinal analyses will explore whether the floor effects in participants with symptomatic FTLD will affect the utility for monitoring."

REFERENCE
1. Staffaroni AM, Clark AL, Taylor JC et al. Reliability and validity of smartphone cognitive testing for frontotemporal lobar degeneration. JAMA Netw Open. 2024;7(4):e244266. doi:10.1001/jamanetworkopen.2024.4266