Taylor, Jack C.

ImportanceFrontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD.ObjectiveTo evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations.Design, Setting, and ParticipantsIn this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)–based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes.ExposureParticipants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests.Main Outcomes and MeasuresInternal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy.ResultsIn the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized β range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, −2.49 [95% CI, −0.19 to −0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back β = −0.49 [95% CI, −0.72 to −0.25]; P < .001) but not a composite of traditional neuropsychological measures (β = −0.14 [95% CI, −0.42 to 0.14]; P = .32).Conclusions and RelevanceThe findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.

AbstractBackgroundThere has been a rise in remote cognitive testing for neurodegenerative diseases. The ALLFTD Mobile App is designed to capture clinical features of frontotemporal dementia (FTD) through repeated remote assessment on smartphones. This is a departure from traditional neuropsychological practice in which a single examiner‐led assessment occurs in a controlled setting. When participants complete tasks on their own, those with greater disease severity may be more variable in their performance for a variety of reasons (e.g. greater distractibility, less engagement). Here we study whether intraindividual cognitive variability (IIV) is associated with older age and increasing disease severity.MethodParticipants were 279 (mean age = 54.9) healthy controls and participants with sporadic FTD or from familial FTD kindreds with a range of disease severities based on FTLD Clinical Dementia Rating scale (CDR®+NACC‐FTLD Global) scores: 0 (n = 132), 0.5 (n = 54), and ≥1 (n = 47). Participants completed three cognitive tasks at least two times across twelve days. Measures included an adaptive memory task and gamified versions of Flanker and Go/no‐go tasks. IIV was operationalized as the standard deviation in performance on each task. Regression analyses investigated the relationship of IIV with CDR®+NACC‐FTLD group, and with age in those without symptoms. Education and gender were included as covariates in all analyses.ResultGreater disease severity (CDR®+NACC‐FTLD) was associated with greater variability on Flanker (p<.001) and Go/No‐go (p = .02) tasks; a positive but non‐significant association was seen with memory testing (p = .16). Post‐hoc comparisons found that those with CDR®+NACC‐FTLD of 0.5 had significantly more IIV on the Flanker task (𝛃 = .39, p = .004) than those with CDR®+NACC‐FTLD’s of 0. Moreover, those with a CDR®+NACC‐FTLD ≥1 had significantly greater IIV on the Flanker (𝛃 = .85, p<.001) and Go/No‐go tasks (𝛃 = .51, p = .007) than those with a CDR®+NACC‐FTLD of 0. In those without symptoms (CDR®+NACC‐FTLD = 0), age was associated with increased IIV on the Flanker (𝛃 = .27, p<.001) and Go/no‐go (𝛃 = .23, p<.001) tasks.ConclusionIncreased IIV, particularly on processing speed/executive functioning tasks, was associated with greater age and greater functional impairment, even in the mildest stages. Future investigations exploring predictors of IIV and the prognostic value of IIV are warranted.

AbstractBackgroundFrontotemporal dementia (FTD) is a leading cause of dementia in individuals under age 65. Due to limitations in access to in‐person evaluations, there is an urgent need to examine remote, accessible, and low‐burden assessment techniques for FTD. Unobtrusive monitoring of at‐home computer use in older adults has shown that those with mild cognitive impairment (MCI) have significant declines in computer use over time. To extend these findings, we characterized daily trajectories in smartphone battery percentage, a proxy of smartphone use, and examined relationships with clinical indicators of disease severity in FTD.MethodParticipants included 250 adults enrolled in the ALLFTD Mobile App study (mean age = 53.9 [SD = 14.9]; 59% women; 94% White). To assess clinical disease severity, all participants completed the FTLD Clinical Dementia Rating scale (CDR®+NACC FTLD), a brief neuropsychological battery, the Neuropsychiatric Inventory Questionnaire (NPI‐Q), and brain MRI. The ALLFTD Mobile App was installed onto participants’ smartphones for remote, passive, continuous monitoring of smartphone use (average days of monitoring = 82 [range = 7‐541]). Battery percentage was collected every 15 minutes. Linear mixed effects models examined linear, quadratic, and cubic effects of time of day (i.e., hour; modeled as person‐specific random effects) and their interactions with each measure of disease severity on battery percentage. Models covaried for age.Result57% of participants were clinically normal, 21% had MCI, and 22% had dementia. CDR®+NACC FTLD Global score interacted with hour such that participants with MCI and dementia had flatter battery curves (i.e., less change in battery percentage throughout the day – a proxy of less smartphone use) than clinically normal participants (ps<0.001). Additional models showed that worse memory (hour3 x memory score: 𝛃 = 0.59, p<0.001) and executive functioning (hour3 x executive score: 𝛃 = 0.64, p<0.001), more neuropsychiatric symptoms (hour3 x NPI‐Q: 𝛃 = ‐0.22, p = 0.004), and smaller gray matter volumes (controlling for intracranial volume; hour3 x volume: 𝛃 = 0.49, p<0.001) were also statistically significantly related to less battery usage throughout the day.ConclusionThese findings are proof‐of‐concept that passively acquired smartphone data, specifically battery usage, can provide insights about disease progression in FTD. Results support future research focusing on the development of passively collected digital metrics sensitive to clinical declines in neurodegenerative disease.

AbstractBackgroundSmartphone‐based cognitive and motor tests enable frequent remote assessments in observational research studies and clinical trials, limiting travel burden and increasing access to research for underrepresented groups. One such smartphone tool is the ALLFTD Mobile App, which was designed to capture the clinical features of neurodegenerative diseases via a battery of cognitive, speech, and motor tasks. In this study, we focus on recruiting a demographically diverse normative sample. We have partnered with the UCSF Brain Health Registry (BHR) to recruit 1,000 cognitively healthy participants across the lifespan. Here we describe the study design and initial feasibility results.MethodsWe designed an automated workflow in which participants never interact with the study team except for troubleshooting. BHR participants without reported cognitive impairment were contacted by email to participate in this study (n = 668). Interested participants downloaded the app onto their smartphone and completed in‐app electronic consent. They were asked to complete three ∼30‐minute sessions of cognitive, motor and speech measures over two weeks. Adherence was determined by evaluating the completion rate of app tasks. In a subset who completed a user experience questionnaire (n = 116), responses were quantified using descriptive statistics.ResultsThe current enrollment rate is 23.20% (155/668) of contacted participants. Average age is 62 (SD = 8.2, range = 25‐84). Average adherence is 76%. Participants reported a range of perceived task difficulty: 38% indicated tasks were “very easy” or “somewhat easy”, 26% indicated they were “neutral,” 36% found the tasks “somewhat difficult,” and none reported them to be “very difficult.” The time commitment was reported to be acceptable by 97% of participants, and 20% were willing to complete additional tasks. Over half (59%) of participants indicated that they preferred using a smartphone to complete cognitive assessments over traditional pen‐and‐paper measures.ConclusionsOur preliminary results demonstrate the feasibility and acceptability of recruiting participants, including older adults, through a registry and conducting remote smartphone testing via a fully automated workflow that is highly scalable. Future analysis will study the effects of demographic factors on feasibility and investigate the reliability and validity of the app measures in this sample.

AbstractIntroductionRemote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD‐mApp).MethodsA diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC‐FTLD = 0 [N = 101]; prodromal: 0.5 [N = 49]; symptomatic ≥1 [N = 51]; not measured [N = 13]) were asked to complete ALLFTD‐mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys.ResultsIt was feasible for participants to complete the ALLFTD‐mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity was associated with poorer performance across several tests.DiscussionThese findings suggest that the ALLFTD‐mApp study protocol is feasible and acceptable for remote FTD research.HIGHLIGHTS The ALLFTD Mobile App is a smartphone‐based platform for remote, self‐administered data collection. The ALLFTD Mobile App consists of a comprehensive battery of surveys and tests of executive functioning, memory, speech and language, and motor abilities. Remote digital data collection using the ALLFTD Mobile App was feasible in a multicenter research consortium that studies FTD. Data was collected in healthy controls and participants with a range of diagnoses, particularly FTD spectrum disorders. Remote digital data collection was well accepted by participants with a variety of diagnoses.

AbstractBackgroundMotor disturbances are common in patients with a variety of neurodegenerative and neurological syndromes, such as Parkinson’s disease and Frontotemporal Dementia (FTD). Accurately quantifying motoric changes could enable earlier detection and monitoring of these syndromes, and remote quantification may allow for more frequent assessments and may improve access to research for underrepresented and geographically dispersed participants. With these benefits in mind, investigators from the ALLFTD consortium developed smartphone tests of balance and finger tapping speed. Here we present preliminary test‐retest reliability and associations with gold standard tests.MethodThe tasks were analyzed in two independent samples. The first was an in‐person cohort of healthy older adults (n = 7), mild cognitive impairment (MCI, n = 1) and FTD (n = 3) who completed the smartphone standing/balance and finger tapping tests (FTT) twice in person. The second sample included 31 ALLFTD participants with a range of clinical presentations (healthy older adults [n = 11], FTD [n = 5], MCI [n = 2], unknown [n = 13]) who were asked to complete the balance test three times over two weeks at home. The primary outcomes were total taps for the FTT and root mean squared acceleration for the balance test. Test‐retest reliability was calculated using an intraclass correlation coefficient (ICC); given the small sample size, outliers (n = 6) were removed from the balance test. We tested the association of smartphone FTT with the gold standard mechanical FTT and the balance task with the CDR®+NACC‐FTLD‐SB (disease severity) using Spearman’s correlations. A Wilcoxon‐sign rank test compared participants with motor features on the Progressive Supranuclear Palsy Rating Scale (PSPRS>0) to those without (PSPRS = 0).ResultThe smartphone FTT showed good test‐retest reliability (ICC = 0.78) and a strong correlation (r = 0.8,p<0.05) with mechanical FTT. The test‐retest reliability for the balance task was excellent for the remote sample (ICC = 0.97) and in‐person (ICC = 0.89) samples. In the remote sample, greater acceleration was correlated with higher CDR®+NACC‐FTLD‐SB (r = 0.7,p = 0.003), and participants with motor features on the PSPRS had higher acceleration than those without (W = 11,p = 0.04).ConclusionThese findings provide preliminary support for the reliability and validity of the ALLFTD Mobile App tests of motor function. Replication in a larger sample is required.

AbstractBackgroundFrontotemporal dementia (FTD) is a collection of neurodegenerative diseases affecting behavior, cognition, and motor functions. FTD treatment trials will benefit from sensitive assessments capable of detecting and longitudinally tracking cognitive changes. Remote smartphone cognitive tests may improve the sensitivity to detect and monitor cognitive decline via novel methods of data capture and more frequent assessments within ecologically valid environments, while simultaneously reducing patient burden. The first step in determining the utility of these measures is establishing their reliability. We previously reported baseline reliability estimates for the ALLFTD Mobile App cognitive tests in a small pilot sample. Here we extend these results using a larger sample and evaluate six‐month stability.MethodWe enrolled a diagnostically mixed sample of 128 participants (CDR®+NACC‐FTLD = 0 [n = 84]; CDR®+NACC‐FTLD = 0.5 [n = 21]; CDR®+NACC‐FTLD≥1 [n = 23]) from ongoing studies of healthy aging (Hillblom Network) and frontotemporal dementia (ALLFTD). Participants self‐administered five cognitive tests from the ALLFTD Mobile App on their own smartphone; they were asked to complete each test three times within two weeks. Tests included gamified versions of N‐back, Stroop, Flanker, and Go/No‐Go paradigms, and an adaptive short‐term memory test. We evaluated the internal consistency of each test’s first occurrence using Spearman‐Brown split‐half reliability (100 simulations). Test‐retest reliability over the first three baseline replicates (as available) was evaluated by calculating intraclass correlations (ICC). In a preliminary analysis, we tested the six‐month stability of test performance in nine functionally intact participants who completed baseline and follow‐up Flanker, N‐Back, and adaptive memory assessments by calculating Spearman’s rho.ResultSplit‐half reliability estimates were in the good to excellent range (r’s: 0.81–0.97). Test‐retest reliability estimates were in the adequate to excellent range (ICCs: 0.72–0.96). ICC estimates were comparable for participants with and without clinical impairment (CDR®+NACC‐FTLD = 0 (0.74–0.95) and CDR®+NACC‐FTLD >0 (0.67–0.95). Among functionally intact individuals, baseline and 6‐months scores were highly correlated (r’s: 0.76–0.93, p’s<.05).ConclusionOur findings of adequate to excellent internal consistency, test‐retest reliability, and 6‐month stability support the feasibility of remote, smartphone‐based cognitive testing among a diagnostically mixed sample typical of healthy aging and frontotemporal dementia research studies.

AbstractBackgroundRemote digital cognitive assessments validated for use in frontotemporal dementia (FTD) and other neurodegenerative diseases would benefit clinical trials and clinical care. The ALLFTD Mobile App includes several smartphone‐based measures of cognition, and prior studies have provided preliminary support for their reliability. Here we evaluate their validity by testing associations with gold standard clinical outcomes and expected neural correlates.MethodA diagnostically mixed sample of 92 participants (CDR®+NACC‐FTLD = 0 [n = 33]; CDR®+NACC‐FTLD = 0.5 [n = 15]; CDR®+NACC‐FTLD≥1 [n = 16]; unknown [n = 28]) were recruited from a UCSF healthy aging study (Hillblom Network) and a North American FTD study (ALLFTD). Participants were asked to remotely complete four ALLFTD Mobile App tests of executive functioning (EF) and a memory test on their smartphones. Gold standard clinical measures were also collected; outcomes were the UDSv3 EF composite, CVLT‐SF Total Immediate Recall (memory), and CDR®+NACC‐FTLD Box Score (disease severity). Volumetric brain MRI measurements were available for a subset (n = 37). Expected neural correlates were frontoparietal gray matter volume for EF tests and hippocampal volume for the memory test. Linear models were fitted to evaluate the association of app tests with the gold standard outcomes, controlling for education, sex, and total intracranial volume (imaging only).ResultSmartphone EF measures were strongly and positively associated with the UDS3‐EF composite (ß’s = 0.6–0.8, all p<.001). The memory test was strongly correlated with the CVLT‐SF (ß = 0.7, p<.001). Tests were less strongly associated with divergent cognitive domains (e.g., associations with a visuospatial test were ß’s = 0.1–0.3). Worse performance on all tests was significantly associated with greater disease severity (ß’s = 0.5–0.7, all p<.001). Worse app‐based EF scores were associated with lower frontoparietal volume (ß’s = 0.4–0.6, all p<.015) and worse memory scores with lower hippocampal volume (ß = 0.5, p<.001).ConclusionALLFTD Mobile App scores were strongly associated with gold standard neuropsychological tests of the same cognitive domain (i.e., convergent validity) and less associated with measures of a different domain (i.e., divergent validity). Worse performance on the smartphone tests was associated with increasing disease severity and volume loss in expected brain regions. These results provide preliminary support for the construct validity of the ALLFTD Mobile App cognitive tests.

ImportancePhysical activity is associated with cognitive health, even in autosomal dominant forms of dementia. Higher physical activity is associated with slowed cognitive and functional declines over time in adults carrying autosomal dominant variants for frontotemporal lobar degeneration (FTLD), but whether axonal degeneration is a potential neuroprotective target of physical activity in individuals with FTLD is unknown.ObjectiveTo examine the association between physical activity and longitudinal neurofilament light chain (NfL) trajectories in individuals with autosomal dominant forms of FTLD.Design, Setting, and ParticipantsThis cohort study included individuals from the ALLFTD Consortium, which recruited patients from sites in the US and Canada. Symptomatic and asymptomatic adults with pathogenic variants in one of 3 common genes associated with FTLD (GRN, C9orf72, or MAPT) who reported baseline physical activity levels and completed annual blood draws were assessed annually for up to 4 years. Genotype, clinical measures, and blood draws were collected between December 2014 and June 2019; data were analyzed from August 2021 to January 2022. Associations between reported baseline physical activity and longitudinal plasma NfL changes were assessed using generalized linear mixed-effects models adjusting for baseline age, sex, education, functional severity, and motor symptoms.ExposuresBaseline physical activity levels reported via the Physical Activity Scale for the Elderly. To estimate effect sizes, marginal means were calculated at 3 levels of physical activity: 1 SD above the mean represented high physical activity, 0 SD represented average physical activity, and 1 SD below the mean represented low physical activity.Main Outcomes and MeasuresAnnual plasma NfL concentrations were measured with single-molecule array technology.ResultsOf 160 included FTLD variant carriers, 84 (52.5%) were female, and the mean (SD) age was 50.7 (14.7) years. A total of 51 (31.8%) were symptomatic, and 77 carried the C9orf72 variant; 39, GRN variant; and 44, MAPT variant. Higher baseline physical activity was associated with slower NfL trajectories over time. On average, NfL increased 45.8% (95% CI, 22.5 to 73.7) over 4 years in variant carriers. Variant carriers with high physical activity demonstrated 14.0% (95% CI, −22.7 to −4.3) slower NfL increases compared with those with average physical activity and 30% (95% CI, −52.2 to −8.8) slower NfL increases compared with those with low physical activity. Within genotype, C9orf72 and MAPT carriers with high physical activity evidenced 18% to 21% (95% CI, −43.4 to −7.2) attenuation in NfL, while the association between physical activity and NfL trajectory was not statistically significant in GRN carriers. Activities associated with higher cardiorespiratory and cognitive demands (sports, housework, and yardwork) were most strongly correlated with slower NfL trajectories (vs walking and strength training).Conclusions and RelevanceIn this study, higher reported physical activity was associated with slower progression of an axonal degeneration marker in individuals with autosomal dominant FTLD. Physical activity may serve as a primary prevention target in FTLD.