Sanderson‐Cimino, Mark

Introduction: Frontotemporal lobar degeneration (FTLD) is a devastating disease that commonly results in early onset dementia, yet its rarity and heterogeneity limit large-scale research and clinical trials. Remote monitoring via low-burden digital health tools may overcome these barriers. We evaluated clinical utility of passive smartphone monitoring in FTLD using a multi-domain mobile assessment platform. Methods: Participants were 567 adults (53% clinically normal, 21% prodromal FTLD, 26% symptomatic FTLD) who completed an in-person study visit and downloaded the ALLFTD Mobile App on their personal smartphones. The app delivered unsupervised cognitive tests and passively collected continuous data on battery percentage (proxy for smartphone use) and step count. Longitudinal follow-up included smartphone monitoring and annual in-person study visits. Primary analyses examined associations between passive smartphone features and markers of disease severity at baseline and longitudinally, and tested whether passive features added incremental value beyond app-based cognitive testing. Results: Passive smartphone features were feasible to collect and showed excellent reliability with <2 weeks of monitoring (ICCs>0.9). Features capturing smartphone use and movement demonstrated sensitivity to gold-standard clinical measures of disease severity both at baseline and longitudinally. A classification model combining passive features, the app-based cognitive composite score, and demographics detected longitudinal functional decline (AUC=0.89); passive features alone (AUC=0.84) performed comparably to a cognitive screener (AUC=0.85). Discussion: Passive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing. Findings support its use as a scalable digital endpoint in longitudinal FTLD research.

Background Motor disturbances are common in neurologic and neurodegenerative syndromes. A standard motor speed and dexterity measure is the finger tapping test (FTT). The FTT has traditionally been administered in clinic using a mechanical FTT, limiting accessibility and early motor change quantification. This study assessed the validity of a smartphone app-based FTT, which may expand access and enable more frequent testing. Methods The cohort was diagnostically diverse, including participants with frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal syndrome, primary progressive aphasia, multiple sclerosis, and clinically unimpaired controls. Participants completed a 20-second ALLFTD Mobile App (mApp)-FTT with each hand. Tapping speed metrics were extracted. Participants completed the gold-standard mechanical FTT, a neurologist-administered finger tapping exam, the PSP Rating Scale (PSPRS) and the Unified Parkinson’s Disease Rating Scale (UPDRS). Correlations assessed mApp-FTT and mechanical FTT relationships; regressions evaluated associations with neurologist-rated finger tapping impairment, PSPRS and UPDRS, adjusting for age and sex. Results The mApp-FTT showed moderate-to-strong correlations with the mechanical FTT (dominant: r=0.63, p<0.001; non-dominant: r=0.55, p<0.001). Taps per second were associated with PSPRS motor severity (dominant hand: std. β=-0.59, 95% CI [-0.91, -0.27], p<0.001) and the UPDRS (dominant hand: std. β=-0.41, 95% CI [-0.82, 0.00], p=0.049). Flight time was modestly associated with neurologist-rated finger tapping impairment (dominant hand: std. β=0.15, 95% CI [0.00, 0.29], p=0.044). Conclusion These findings support mApp-FTT validity as a measure of motor function across neurodegenerative conditions. Validation in longitudinal and unsupervised remote settings is warranted to understand scalability and evaluate change over time.

Importance TMEM106B is a frontotemporal lobar degeneration (FTLD) genetic susceptibility factor, and TMEM106B protein aggregates are a feature of aging and neurodegeneration. Whether TMEM106B protein levels are associated with clinical features is unknown. Objective To investigate the clinical associations of cerebrospinal fluid (CSF) TMEM106B in FTLD. Design, Setting, and Participants This cross-sectional study was conducted in 2 independent frontotemporal dementia (FTD) cohorts (recruitment from April 2009 through July 2023, with analyses from January 2025 through April 2026), with a 2-year follow up. This multicenter clinical study integrated clinical, genetic, biomarker, and neuroimaging data. Individuals were recruited through the University of California, San Francisco (n = 3733), or ALLFTD (n = 2343). Participants with available CSF were included. A discovery cohort (n = 271) included participants with sporadic neuropathology-confirmed FTLD; presymptomatic or symptomatic carriers of pathogenic variants in C9orf72 , GRN , or MAPT ; or controls. An independent validation cohort (n = 383) included participants with clinically diagnosed sporadic FTD, Alzheimer disease (AD), and controls. Exposures CSF samples for TMEM106B quantification with aptamer proteomics (SomaScan version 3.0 [discovery cohort] and SomaScan version 4.1 [validation cohort]). Main Outcomes and Measures Parametric tests compared the primary outcome, CSF TMEM106B, by disease severity, TMEM106B rs1990622 genotype, sex, clinical syndrome, pathological diagnosis, and pathogenic variant and determined associations with brain volume. Results In the discovery (n = 271; 136 women [51%]; median [IQR] age, 59 [38-80] years) and validation (n = 383; 183 women [48%]; median [IQR] age, 64 [50-78] years) cohorts, lower CSF TMEM106B was associated with more severe disease (β, −0.15; 95% CI, −0.24 to −0.04; P = .003), lower frontotemporal brain volumes (β, 0.42; 95% CI, 0.24-0.61; P &amp;lt; .001), and faster clinical progression (β, −2.21; 95% CI, −3.70 to −0.72; P = .001). Associations of TMEM106B with clinical disease severity were independent of those with neurofilament light chain. TMEM106B levels were influenced by TMEM106B rs1990622 genotype, where individuals with the protective G/G genotype had lower levels than the risk A/A genotype. CSF TMEM106B levels did not differentiate between FTLD subtypes or between FTLD and AD. Conclusions and Relevance Per the results of this cross-sectional study, TMEM106B is detectable in CSF and levels reflect disease severity in sporadic and genetic FTLD and AD, but levels are also influenced by the TMEM106B rs1990622 genotype. CSF TMEM106B could support further studies to understand the mechanisms of disease and develop clinical tools in FTLD and other neurodegenerative diseases.

Abstract BACKGROUND Remote, smartphone‐based cognitive testing may improve access to cognitive assessments for Alzheimer's disease and related dementias. We evaluated the feasibility, reliability, and validity of unsupervised smartphone‐based cognitive tests in a registry‐based cohort. METHODS Adults without a record of cognitive impairment ( N = 1815; ages 18–92) were recruited from the University of California, San Francisco (UCSF) Brain Health Registry to complete three unsupervised smartphone cognitive testing sessions within 2 weeks. Reliability was assessed with correlations between sessions. Linear regression models tested associations of smartphone tasks with demographics, self‐ and informant‐rated cognitive concerns, and web‐based cognitive testing (Cogstate Brief Battery). RESULTS Adherence was high (82.2%) and usability favorable. Test–retest reliability was moderate to strong ( ρ ’s = 0.61–0.85, all p ’s < 0.001). Lower smartphone scores were associated with older age, lower education, cognitive concerns, and worse Cogstate performance. DISCUSSION Findings support the feasibility, reliability, and validity of remote digital assessments in adults without a record of cognitive impairment.

Abstract Background TMEM106B encodes a lysosomal protein and is a genetic susceptibility factor for frontotemporal lobar degeneration (FTLD). Aptamer‐based proteomics quantifies TMEM106B protein levels in CSF. The associations of CSF TMEM106B with measures of disease severity have not been previously evaluated, and the value of CSF TMEM106B as a clinical biomarker is unknown. Method CSF TMEM106B and NfL protein levels were quantified with aptamer‐based proteomics in participants from two independent cohorts: sporadic FTLD with neuropathology‐confirmed FTLD‐tau and FTLD‐TDP, clinically diagnosed PSP‐Richardson Syndrome, and controls (UCSF MAC, n = 95; mean age = 69 ± 6 yrs; 48% female) and familial FTLD comprised of presymptomatic and symptomatic FTLD mutation carriers with family non‐carrier controls (ALLFTD, n = 179; mean age = 49 ± 13 yrs; 53% female). The association between biomarkers and diverse measures of disease severity, including the CDR®+NACC‐FTLD and CDR®+NACC‐FTLD sum of boxes, were determined with linear regressions or mixed linear models. Associations with brain volumes were determined within the framework of voxel‐based morphometry. Result In both cohorts, at baseline, CSF TMEM106B did not differ by sex, age, FTLD phenotype, or CSF NfL. CSF TMEM106B was lower in cases with worse disease severity (Figure 1) and in participants with the protective TMEM106B rs1990622 G/G genotype, regardless of pathological diagnosis or FTLD‐causing mutation. Low CSF TMEM106B was associated with more severe longitudinal worsening in FTLD disease severity (Figure 2), basic and instrumental function, global cognition, executive function, and depression scores. These associations were weaker than those of NfL. Low CSF TMEM106B was associated with low brain volumes in frontal, parietal, and temporal regions (FWE‐corrected p < 0.05) (Figure 3A). CSF NfL negatively correlated (FWE‐corrected p < 0.05) with brain volumes in frontotemporal regions (Figure 3B). Conclusion CSF TMEM106B concentrations are influenced by the TMEM106B rs1990622 genotype, and correlate with disease severity and brain volume in both genetic and sporadic FTLD. Lower levels of CSF TMEM106B correlate with more severe disease and brain atrophy. Disease severity is more strongly associated with CSF NfL, while brain volumes are more strongly associated with CSF TMEM106B. CSF TMEM106B may have value as a biomarker of neurodegeneration in FTLD.

Abstract Background Motor disturbances are common in neurodegenerative disorders. Digital health technologies can be a tool for remote, accessible, and low‐burden motor assessments. The ALLFTD Mobile App includes a finger‐tapping test (mApp‐FTT) to assess dexterity. We evaluated the reliability and construct validity of smartphone‐based measures of finger tapping in an in‐person sample. Methods Participants ( n = 33; mean age=68.2 [SD=8.6]) completed the mobile finger‐tapping test (mApp‐FTT) on iOS and Android devices (two counterbalanced 20‐second trials per hand) and the mechanical finger‐tapping test (FTT). The sample included cognitively unimpaired participants (22.2%) and those diagnosed with frontotemporal dementia‐spectrum disorders (41.7%), Alzheimer's dementia (22.2%), and progressive supranuclear palsy or corticobasal syndrome (13.9%). A motor domain was calculated based on neurological exam and added to the Clinical Dementia Rating® plus National Alzheimer's Coordinating Center–Frontotemporal Lobar Degeneration (CDR®+NACC‐FTLD). Pearson's correlations assessed associations between mApp‐FTT performance and FTT performance, clinical severity (CDR®+NACC‐FTLD Box Score), motor rating scales (Progressive Supranuclear Palsy Rating Scale [PSPRS] and Unified Parkinson's Disease Rating Scale [UPDRS]), and cognitive function. Due to small sample size, PSPRS subdomains were dichotomized, and t‐tests were performed to evaluate group differences based on symptom presence. Results Total mApp‐FTT taps on iOS and Android were strongly correlated ( r = 0.86, 95% CI [0.76, 0.92], p < .001). mApp‐FTT was associated with manual FTT on iOS ( r = 0.70, 95% CI [0.52, 0.82], p < .001) and Android ( r = 0.62, 95% CI [0.41, 0.77], p < .001). Among iOS users, total PSPRS score was negatively correlated with mApp‐FTT ( r = ‐0.60, 95% CI [‐0.75, ‐0.39], p < .001). Worse mApp‐FTT performance was observed in participants with higher limb rigidity (mean difference=15.46, 95% CI [3.40, 27.52], p < .001), limb dystonia (mean difference=19.22, 95% CI [5.67, 32.77], p < .001), and finger tapping (mean difference=12.74, 95% CI [3.42, 22.06], p < .001). Total UPDRS score correlated with lower mApp‐FTT ( r = ‐0.48, 95% CI [‐0.66, ‐0.28], p < .001), as did disease severity (CDR®+NACC‐FTLD Box Score; r=‐0.46, 95% CI [‐0.66, ‐0.22], p < .001). Conclusion Smartphone‐based finger‐tapping assessments effectively detect motor and cognitive impairment, with stronger associations for motor function. Findings in iOS users highlight the need to assess operating system‐related biases and validate in Android. Remote smartphone assessments offer a scalable tool for tracking disease progression, warranting larger longitudinal studies.

Abstract Objective: The National Institutes of Health (NIH) Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) is a validated laptop-based battery of executive functioning tests. A modified tablet version of the EXAMINER was developed on the UCSF Tablet-based Cognitive Assessment Tool (TabCAT-EXAMINER). Here we describe the battery and investigate the reliability and validity of a composite score. Methods: A diagnostically heterogeneous sample of 2135 individuals (mean age = 65.58, SD = 16.07), including controls and participants with a variety of neurodegenerative syndromes, completed the TabCAT-EXAMINER. A composite score was developed using confirmatory factor analysis and item response theory. Validity was evaluated via linear regressions that tested associations with neuropsychological tests, demographics, clinical diagnosis, and disease severity. Replicability of cross-sectional results was tested in a separate sample of participants ( n = 342) recruited from a frontotemporal dementia study. As this separate sample also collected longitudinal TabCAT-EXAMINER measures, we additionally assessed test-retest reliability and associations between baseline disease severity and changes in TabCAT-EXAMINER scores. Results: The TabCAT-EXAMINER score was normally distributed, demonstrated high test-retest reliability, and was associated in the expected directions with independent tests of executive functioning, demographics, disease severity, and diagnosis. Greater baseline disease severity was associated with more rapid longitudinal TabCAT-EXAMINER decline. Conclusions: The TabCAT-EXAMINER is a tablet-based executive functioning battery developed for observational research and clinical trials. Performance can be summarized as a single composite score, and results of this study support its reliability and validity in cognitive aging and neurodegenerative disease cohorts.

AbstractBackgroundSubjective cognitive concerns are common in functionally intact adults, potentially indicating future cognitive decline. Remote smartphone cognitive testing holds promise for objectively tracking cognition in individuals reporting complaints. In our initial exploration of the link between subjective cognitive complaints and digital clinical outcomes, we examined participants' self‐reported cognitive complaints' association with smartphone tests on memory and executive functioning.MethodsParticipants, without self‐reported MCI or dementia, were recruited from the UCSF Brain Healthy Registry (BHR) to complete cognitive tasks on their personal smartphone with the ALLFTD Mobile App. Participants also completed the 12‐item Everyday Cognition Screening Tool (ECog‐12), assessing subjective cognitive impairment, online as part of BHR. Average ECog‐12 scores, including Memory and Executive Functioning subdomains, were calculated. Correlations between scores from online ECog‐12 scores and app‐based smartphone tasks were examined. Regression analyses, adjusting for age, education, and sex, were performed to evaluate the relationship between ECog‐12 and smartphone tasks (Stroop & Flanker) measuring executive function and memory.ResultsOut of 2,283 invited BHR participants, 456 (mean age: 64.6 years (SD=11.8) and education: 16.3 years (SD=2.4)) completed smartphone tasks (81.1% completion rate). Age was negatively associated with executive functioning and memory tasks (β’s=‐0.51 to ‐0.54, p’s<0.05), while higher education correlated with better performance (β’s=0.10‐0.14, p’s<0.05). Sex was not significantly associated with performance on any task (β’s=‐0.04 to 0.09, p’s>0.05). Subjective cognitive concerns were linked to tasks of executive functioning (Stroop: β=‐0.18, p=0.002) and memory (β=‐0.14, p=0.02). Endorsement of executive functioning items on ECog‐12 associated with Stroop performance (β=‐0.16, p=0.005), and memory‐specific complaints were related to memory performance (β=‐0.1, p=0.09). The relationship with flanker scores was not significant (β=‐0.08, p=0.17). Similar patterns emerged with the online ECog‐12; online and app‐based scores are strongly correlated (β=0.75, p<0.05).ConclusionsIn this cognitively intact sample, subjective cognitive concerns were linked to poorer performance on ALLFTD Mobile App tasks assessing executive functioning and memory. These findings suggest that unsupervised remote smartphone testing merits further consideration to monitor cognition in individuals with subjective cognitive concerns. Subsequent studies in deeply phenotyped cohorts with follow‐up assessments are essential for understanding the clinical relevance of these results.

AbstractBackgroundThe earliest cognitive manifestations of asymptomatic and prodromal familial frontotemporal dementia (f‐FTD) mutation carriers are still being characterized. Patients with symptomatic FTD are known to be error prone, particularly on tasks of executive function, but little is known about the frequency or predictive utility of these errors in the earliest stages of f‐FTD. The current study compared error rates on executive functioning tasks in controls and asymptomatic and prodromal mutation carriers and investigated whether errors predict worsening clinical status as follow up.MethodThis study included 90 participants (mean age = 48.57, SD = 13.30; 51.1% female; 86.67% white) with pathogenic FTD mutations (C9orf72, n = 45; GRN, n = 30; or MAPT, n = 15) who were asymptomatic or prodromal (Clinical Dementia Rating plus FTLD; CDR®+NACC‐FTLD ≤ 0.5). Propensity score matching identified (CDR®+NACC‐FTLD = 0) who did not carry pathogenic mutation but were matched on age, education, and sex. Regressions were used to compare controls and mutation carriers on error scores (rule violations and/or repetitions) from three executive functioning tasks: design fluency, lexical fluency, and Stroop inhibition. Mutation carriers with longitudinal data within 1.5 years were binarized as stable (n = 35) or progressors (n = 13) based on whether their CDR®+NACC‐FTLD sum of boxes score was worse at follow up (mean follow up = 1.07 years). Regressions were fit to evaluate the relationship between baseline error scores and group (i.e., stable vs. progressor).ResultMutation carriers committed significantly more errors than controls on the Stroop task (β = 0.67, p = 0.03) and lexical fluency (repetitions: β = 0.27, p = 0.02). The groups did not significantly differ in errors on the remaining tasks. A greater number of Stroop errors predicted mutation carriers who progressed at follow up (β = 1.04, p<0.001). When introducing the primary outcome from each task as a covariate (e.g., correct responses), the fluency task (repetitions: β = 0.10, p = 0.03) and Stroop task (errors: β = 0.82, p<0.001) were significantly associated with progression.ConclusionErrors on executive tasks may be early cognitive features in familial FTD. Importantly, errors were uniquely predictive above and beyond total scores. Research in larger samples will enable investigations of genetic differences in error rates.

AbstractBackgroundMany treatments targeting frontotemporal lobar degeneration (FTLD) are in the developmental pipeline, but the rarity of the disease, coupled with the behavioral and motor features of FTLD, make it challenging to identify sufficient trial participants who can attend frequent in‐person visits. Decentralized clinical trial designs with remote evaluations are attractive alternatives but require validated tools for symptom tracking. Our previous cross‐sectional analyses showed that cognitive tasks deployed via the ALLFTD Mobile App are reliable and sensitive to early stages of disease. The current study seeks to evaluate whether unsupervised smartphone cognitive tests are sensitive to longitudinal changes that occur with increasing FTLD disease stage.MethodThe study included 194 participants (mean baseline age 54.30, SD = 15.66; mean education = 16.52, SD = 2.31; 55.2% women) who were asymptomatic (Clinical Dementia Rating plus FTLD (CDR®+NACC‐FTLD) = 0 [n = 109; 43 carriers of FTLD‐associated genetic variants]), prodromal (CDR®+NACC‐FTLD = 0.5 [n = 39]), or symptomatic (CDR®+NACC‐FTLD>0.5 [n = 46]) at baseline. Participants completed ALLFTD Mobile App smartphone versions of Stroop, flanker, and 2‐back tasks, as well as an adaptive associative memory task, every six months for up to two years. Linear‐mixed effects models investigated the effect of disease severity on cognitive trajectories by testing the interaction of baseline CDR®+NACC‐FTLD box score and time on smartphone test scores. Analyses were repeated in the subsample of asymptomatic/prodromal CDR®+NACC‐FTLD<1) familial FTLD mutation carriers (C9orf72, n = 27; MAPT, n = 16). All models controlled for age, education, and sex.ResultGreater baseline disease severity was associated with lower cognitive scores across all tasks (β range: ‐0.28 to ‐0.13; p’s < 0.001), and faster rates of decline on the memory and 2‐back tasks (β range: ‐0.15 to ‐0.07; p’s<0.04). When the sample was restricted to asymptomatic and prodromal individuals (CDR®+NACC FTLD<1), greater baseline disease severity was still associated with lower scores across most tasks (β range: ‐0.48 to ‐0.27; p’s<0.002; 2‐back: β = ‐0.19, p = 0.26). When the sample was restricted to asymptomatic/prodromal mutation carriers, disease severity remained associated with the memory and flanker tasks (β range: ‐0.85 to ‐0.45; p’s<0.01).ConclusionThis study provides initial evidence that longitudinal smartphone‐based cognitive measurements capture the accelerated cognitive worsening that accompanies increasing disease progression in FTLD.