Citations

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 Frontotemporal dementia (FTD) is characterized by selective neuronal vulnerability, yet the features that predispose specific neuron types to degeneration remain unclear. We performed single-nucleus RNA sequencing of frontoinsular cortex, a region affected early in behavioral variant FTD, across individuals with C9orf72 -associated and sporadic FTD-MND spectrum disease. By enriching for large projection neurons, we resolved molecular subtypes of layer 5 extratelencephalic neurons, including von Economo neurons, and identified selective depletion of specific layer 2/3 and layer 5 neuron subtypes, convergent across genotypes. Despite selective neuronal loss, disease-associated transcriptional changes were convergent across excitatory neuron populations, suggesting that they reflect upstream pathophysiology or shared responses to local neurodegeneration. By relating neighborhood-level depletion in disease to gene expression in controls, we found that baseline cellular respiration and ATP synthesis predict neuronal vulnerability in disease. These findings define molecular correlates of selective neuronal vulnerability in FTD and provide a framework linking cell type and state to neurodegeneration.

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.

Objective Age of symptom onset is highly variable in familial frontotemporal lobar degeneration (f‐FTLD). Accurate prediction of onset would inform clinical management and trial enrollment. Prior studies indicate that individualized maps of brain atrophy can predict conversion to dementia in f‐FTLD. We used a Bayesian linear mixed‐effect (BLME) prediction method for identifying accelerated brain volume loss to predict conversion to dementia. Methods Participants included 234 asymptomatic or prodromal carriers of C9orf72 , GRN , or MAPT mutations (including 21 dementia converters) with ≥3 longitudinal magnetic resonance imaging (MRI) T1‐weighted scans. The BLME models established individual voxel‐wise gray matter trajectories using the first 2 scans. Person‐specific clusters of accelerated volume loss were estimated in subsequent scans and tested as predictors of dementia conversion compared with other approaches in time‐varying Cox proportional hazard models covarying for age. Receiver‐operating characteristic (ROC) curves estimated utility of cluster volume in discriminating which participants converted to dementia within 24 months. Results The BLME cluster volume predicted conversion to dementia in f‐FTLD mutation carriers overall and separately in C9orf72 , GRN , and MAPT , with comparable hazard ratios observed for atrophy W‐maps and regional volumes. Within a 24‐month timeframe, BLME cluster volume discriminated dementia converters from non‐converters with larger areas under the curve (AUCs) than other approaches. Interpretation Bayesian‐modeled individualized atrophy scores predict dementia progression among asymptomatic f‐FTLD mutation carriers and may have increased utility compared with other structural imaging methods when studying individuals over shorter timeframes that align with clinical trial design. ANN NEUROL 20269999:n/a–n/a

Abstract Background Previous studies demonstrate that certain asymptomatic MAPT variant carriers (Asymp‐ MAPT ) exhibit altered baseline gray matter volume (GMV) and functional connectivity (FC) profiles. It remains unclear whether these imaging measures may herald risk for earlier conversion to the symptomatic phase. To address this, we stratified Asymp‐ MAPT based on baseline GMV and longitudinal FC changes to assess whether any Asymp‐ MAPT subgroups showed signs of longitudinal neurodegeneration or cognitive decline. Method We studied 25 Asymp‐ MAPT recruited from the UCSF Memory and Aging Center and ALLFTD Consortia. Using a median split, we divided Asymp‐ MAPT into groups with smaller (LowGMV; n = 12) and larger baseline GMV (HighGMV; n = 13) within regions atrophied in symptomatic MAPT carriers ( n = 20). Next, we stratified Asymp‐ MAPT based on longitudinal FC changes using k‐means clustering on rates of change in FC for four intrinsic connectivity networks associated with common MAPT ‐related syndromes: salience (SN), corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and default mode (DMN) networks. We compared Asymp‐ MAPT subgroups from each stratification on baseline and longitudinal changes in demographics, plasma neurofilament light (NfL) concentration, GMV within 246 Brainnetome regions, and neuropsychological test scores. Result Stratification of Asymp‐ MAPT based on baseline GMV showed that LowGMV had higher education levels compared to HighGMV, with no other demographic differences. Though LowGMV and HighGMV did not differ in baseline NfL, LowGMV showed greater longitudinal NfL increases. These groups did not differ in baseline or longitudinal GMV changes. LowGMV had lower baseline attention and working memory scores, and greater longitudinal decline in set‐shifting and visuospatial performance. Stratification based on FC changes yielded one group (DecFC; n = 17) exhibiting longitudinal decreases in the SN, PSP, and DMN and another (IncFC; n = 8) showing increases in each network. DecFC and IncFC did not differ in demographics, baseline or longitudinal NfL, or baseline GMV. Longitudinally, DecFC showed greater decline in posterior superior temporal and inferior parietal cortices. DecFC showed lower baseline attention and semantic fluency scores, and greater longitudinal decline in set‐shifting and visuospatial memory performance. Conclusion Lower baseline GMV within regions atrophied during the symptomatic phase and longitudinal FC declines within MAPT ‐relevant networks may signal earlier symptomatic conversion in Asymp‐ MAPT .

Abstract Background A hexanucleotide repeat expansion in C9orf72 is the leading genetic cause of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. There remains a critical need for biomarkers that track disease progression across clinical stages. Cross‐sectionally, intrinsic connectivity networks (ICNs) derived from task‐free fMRI (tf‐fMRI) detects abnormalities in C9orf72 expansion carriers ( C9orf72+ ), even when brain structural differences are subtle (Lee et al. , 2017). Few studies have examined longitudinal connectivity changes in C9orf72+ , however. Methods We analyzed longitudinal structural and tf‐fMRI data and plasma neurofilament light chain (NfL) concentrations of C9orf72+ recruited from UCSF and the ALLFTD Consortia. Mean time from first to last scan was 2.4±1.3 years. Participants included 36 asymptomatic (aSx‐ C9 ), 17 prodromal (prodromal‐ C9 ), 29 symptomatic (Sx‐ C9 ) carriers, and 107 healthy controls (HC). For structural MRI analyses, smoothed gray matter maps were parcellated into 246 regions‐of‐interest based on the Brainnetome atlas. We conducted voxelwise seed‐based tf‐fMRI analyses to examine ICNs showing alterations C9orf72+ based on previous literature: salience network (SN), sensorimotor network (SMN), default mode network (DMN), and a medial pulvinar thalamus network (pulvinar). General linear models and linear mixed models (LMM) compared C9orf72+ groups to HC in baseline and longitudinal gray matter and functional connectivity, as well as examined associations between longitudinal functional connectivity changes and baseline NfL concentrations. Results Despite a lack of longitudinal gray matter decline, aSx‐ and Sx‐ C9orf72+ showed functional connectivity changes. Compared to HC, aSx‐ C9 had baseline hypoconnectivity in the SN, SMN, and pulvinar network. Longitudinally, this group showed declines in the SN and pulvinar network, alongside DMN increases. Prodromal‐ C9 exhibited baseline SMN hypoconnectivity and hyperconnectivity in the DMN and pulvinar network, but no significant longitudinal changes. Sx‐ C9 showed baseline hypoconnectivity in SN, SMN, and DMN, with additional regions of DMN hyperconnectivity, while longitudinally, SN and SMN connectivity increased. In aSx‐ C9 , higher baseline NfL concentrations correlated with regions of SMN decreases over time and both increases and decreases in the pulvinar network. In prodromal‐ C9 and Sx‐ C9 combined, higher NfL was associated with DMN increases longitudinally. Conclusions Though gray matter declines were undetectable over a span of several years, functional connectivity networks changed dynamically in C9orf72+ .

Abstract Background Frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominant atrophy is an emerging area of interest. Recent findings by the International Working Group (IWG) have identified this subtype as having a distinct clinical profile within the FTD spectrum (Ulugut et al., 2024, A&D). However, its genetic and pathological underpinnings remain unexplored in large, multicultural cohorts. Methods Retrospective analyses encompassing clinical, genetic, pathological, and neuroimaging data from 23 IWG sites across 13 countries in Asia, Middle East, Europe, North and South America were conducted. The study included 444 patients with FTD exhibiting predominant RATL atrophy. Results Genetic screening was performed on 51% ( n = 225) of the cohort for at least the major frontotemporal lobar degeneration (FTLD) mutations including microtubule‐associated protein tau ( MAPT ), progranulin ( GRN ), and chromosome 9 open reading frame 72 ( C9orf72 ), or dementia panels encompassing extended sets of genes. Of these, 81% were sporadic, showing negative results for the screened genes and a modified Goldman Score of ≥ 3, indicating a negative family history for dementia. The MAPT mutation was the most common genetic variant, identified in 7% of the screened cases (Figure 1). Pathological confirmation was available for 63 patients. Among the sporadic cases, transactive response DNA‐binding protein 43 type C (TDP‐C) pathology was most prevalent (60%, n = 32), while tau‐MAPT pathology was most common in the genetic cases (38%, n = 16). Fifteen cases did not fit neatly into genetic or sporadic categories, displaying heterogeneous pathologies (Figure 2). At the initial visit, compared to genetic cases, patients with TDP‐C pathology were older, and more frequently exhibited semantic deficits, with less frequent attention difficulties and executive dysfunction. No differences were observed in sex distribution, symptom duration or disease severity between genetic and sporadic TDP‐C cases. However, left handedness was more common in TDP‐C cases (14%) compared to genetic cases (5%). Conclusion While FTD with RATL atrophy primarily appears sporadic, a significant proportion of cases exhibit genetic variants. These sporadic and genetic subtypes display distinct neuropathological features and clinical manifestations. Given the implications for therapeutic strategies, precise clinical and molecular subtyping is critical for enhancing patient management and ensuring appropriate enrollment in clinical trials.

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.