Paolillo, Emily W.

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.

Abstract Physical activity (PA) is a modifiable lifestyle behaviour associated with lower dementia risk; however, molecular pathways bridging PA-related dementia prevention are poorly understood. We leveraged large-scale plasma proteomics to identify biological signatures of objectively monitored PA and cognitive ageing in functionally intact older adults, cross-validated these signatures in independent exercise cohorts and tested associations with both symptomatic and presymptomatic stages of neurodegeneration across multiple Alzheimer’s disease and related dementias (ADRD) cohorts. We analysed large-scale plasma proteomics data (SomaScan 7k) across three cohorts including naturalistic, objective PA monitoring (University of California, San Francisco Brain Aging Network for Cognitive Health cohort, n = 65), self-reported PA (Atherosclerosis Risk In Communities study, n = 10 644) and PA intervention (Health Risk Factors, Exercise Training and Genetics study, n = 654). Differential regression models examined individual protein correlates of PA, adjusting for age and sex. Weighted gene co-expression network analysis assembled proteins into unbiased modules of protein co-expression, which were annotated for gene ontology and cell-type enrichment. To test clinical relevance to ADRD, we examined PA-related protein levels across-cohorts of symptomatic Alzheimer’s disease and Parkinson’s disease (Stanford Alzheimer’s Disease Research Center), as well as frontotemporal dementia-spectrum disorders (ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium). PA-related plasma proteins were also tested as predictors of antemortem cognitive change and post-mortem brain tissue mass spectrometry proteomic signatures in brain donors from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) cohort. Differential regression and network analyses identified PA plasma proteomic signatures linked to cell adhesion/extracellular matrix (ECM), immune response and lipid metabolism. Protein co-expression module M12 ECM/neurodevelopment harboured growth factor, cell adhesion and vascular remodelling proteins that (i) were positively associated with PA across exercise cohorts, (ii) positively associated with cognitive function and (iii) negatively associated with Alzheimer’s disease, Parkinson’s disease and frontotemporal dementia. Furthermore, M12 was enriched for proteins from Alzheimer’s disease risk genes and antemortem plasma abundance of anthrax toxin receptor cell adhesion molecule 2 (ANTXR2), an M12 ‘hub’ protein and top PA hit across-cohorts, forecasted longitudinal global cognitive decline and post-mortem brain tissue signatures of synaptic function and proteolysis in ROSMAP. Collectively, our integrated systems biology analysis of six independent plasma proteomic datasets facilitated discovery and validation of blood-detectable molecular signatures of PA and neurodegenerative disease, including PA-related proteins with clinical and biological relevance to early stages of disease. Circulating levels of PA-related proteins reflecting ECM biology (e.g. ANTXR2) may represent key molecular targets for dementia prevention.

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.

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 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.

Abstract INTRODUCTION Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD). METHODS Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years. Linear mixed‐effects models investigated how sex and disease stage are associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). RESULTS While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that was not present in symptomatic participants. DISCUSSION In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in the disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD‐causing mutations. Highlights Females with genetic FTD exhibit overall steeper increases in plasma neurofilament light chain (NfL) than males. Females with genetic FTD outperform NfL levels in asymptomatic stages compared to males. Once symptomatic, females with genetic FTD decline more rapidly than males. Plasma NfL is a stronger prognostic marker in asymptomatic males than females.

Abstract The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate ‘pro-aging’ or ‘pro-youthful’ effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer’s disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (Mage = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (Mage = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (Mvisits = 3 years, range 1–7 years) neuropsychological and functional assessments and plasma neurofilament light chain. Our Alzheimer’s disease cohort included 35 adults with sporadic Alzheimer’s disease (Mage = 69.4; 60% female) and 56 controls (Mage = 68.8, 50% female) who completed the same cerebrospinal fluid and clinical outcome measures cross-sectionally. Levels of C-C motif chemokine ligand 11, C-C motif chemokine ligand 2, beta-2-micorglobulin, bone gamma-carboxyglutamate protein (aka Osteocalcin) and colony stimulating factor 2 in cerebrospinal fluid were linearly combined into a composite score, with higher values reflecting ‘pro-youthful’ levels. In genetic frontotemporal dementia, higher baseline cerebrospinal fluid rejuvenation proteins predicted slower decline across cognitive, functional, and neurofilament light chain trajectories; estimates were similar across genotypes. In transdiagnostic analyses, higher cerebrospinal fluid rejuvenation proteins associated with better functional, cognitive, and neurofilament light chain outcomes in adults with sporadic Alzheimer’s disease. Proteins with pre-clinical evidence for brain rejuvenation show translational clinical relevance in adults with Alzheimer’s disease and related dementias and warrant further investigation.

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.