Forsberg, Leah K.

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.

AbstractBackgroundFrontotemporal degeneration (FTD) is an umbrella term encompassing a range of rare neurodegenerative disorders that cause progressive changes to behavior, personality, language, and movement with onset typically before age 60. Currently, several potential FTD therapies are under investigation, underscoring the need for increased diversity in research participation. Two validated scores describe socioeconomic and geographic factors that may impact willingness to participate in research. The Area Deprivation Index (ADI) assesses socioeconomic disadvantages and captures social determinants of health. The Rural‐Urban Commuting Area Codes (RUCA) measures population density, urbanization, and daily commuting to determine individuals living in urban versus rural communities. FTDDR is a compliant, web‐based registry to facilitate FTD research. ADI and RUCA analyses of FTDDR participants can provide insight into current participants’ demographics and areas for recruitment prioritization.MethodFTDDR participants living in the United States were divided into two cohorts: (1‐FTDDR) enrolled in FTDDR only and (2‐ALLFTD) enrolled in FTDDR through ALLFTD, a longitudinal natural history study. ADI was calculated from self‐reported zip codes for 1392 participants in cohort 1 and 983 participants in cohort 2. RUCA scores were generated using self‐reported zip codes for 4565 participants from cohort 1 and 1174 participants from cohort 2.ResultADI analysis showed a low percentage (6.9% FTDDR, 5.7% ALLFTD) of participants lived in highly disadvantageous communities. 40.5% of FTDDR cohort and 49.3% of ALLFTD cohort lived in communities considered “low disadvantage,” suggesting they may have fewer socioeconomic risk factors or impediments to research participation. Most participants in both cohorts lived in urban areas (87.9% FTDDR, 85.8% ALLFD); only 3.2% of both cohorts lived in rural communities.ConclusionSocioeconomic and geographic factors may play a role in accurate diagnosis, access to medical centers, and ability to participate in research. ADI and RUCA analyses indicate that the majority of FTDDR participants, including those actively enrolled in FTD research, live in less disadvantageous neighborhoods and in urban areas, highlighting the need for outreach to more disadvantaged and rural communities. FTDDR prioritizing an engagement strategy to identify, recruit, and retain diverse individuals willing to participate in research could accelerate advancements in FTD research.

AbstractBackgroundAutosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset. However, whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear.MethodUtilizing T1 and task‐free functional magnetic resonance imaging (tf‐fMRI) from 49 presymptomatic and 26 symptomatic GRN mutation carriers, we determined the relationships between functional connectivity as measured by voxel‐wise whole brain degree and GRN‐relevant markers of disease progression, which included plasma neurofilament light chain (NfL) concentrations, CSF complement C1q and C3b protein levels, grey matter atrophy, and OCD symptom severity.ResultNfL concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in presymptomatic GRN carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter, in symptomatic carriers. Presymptomatic carriers with thalamic hyperconnectivity tended to have lower grey matter volume in bilateral insula and left lateral parietal cortex, which are among regions that deteriorate in GRN‐FTD. OCD symptom severity was associated with hypoconnectivity across all GRN carriers.ConclusionIn presymptomatic carriers, the co‐occurrence of hyperconnectivity, high NfL, and low gray matter suggests that tf‐fMRI hyperconnectivity may portend the onset of the neurodegenerative phase. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

AbstractBackgroundThe ALLFTD (ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration) study is an NIH‐funded effort to prepare for clinical trials in sporadic (s‐FTLD) and familial (f‐FTLD) FTLD syndromes by characterizing cohorts, developing new clinical trial outcome measures, and evaluating disease progression. To understand disease trajectories in the context of potential preventative or disease‐modifying therapeutic agents, comprehensive evaluation across multiple time‐points is crucial.MethodALLFTD evaluates participants with FTLD spectrum disorders (bvFTD, svPPA, nfvPPA, FTD‐ALS, CBS, PSP), with strong family histories of FTLD, or known FTLD‐associated genetic variants within the family. ALLFTD has expanded to include 28 expert sites in North America conducting clinical and neuropsychological evaluations, MR Imaging, blood draws, and CSF collection in willing participants, providing detailed data on participant status and disease progression. Participants are asked to return for annual evaluations. The central data management staff assist sites in retention efforts by providing monthly reports of follow‐up visits that are pending, due, or overdue, based on a 15‐month period from previous visit.ResultSince enrollment began in January 2020, ALLFTD has conducted 1363 baseline visits, including 339 participants previously enrolled in ALLFTD’s predecessor studies (ARTFL and LEFFTDS). Excluding individuals not anticipated to return due to disease progression (123), participant death (55), or recent enrollment (<15 months; 318), ALLFTD has a retention rate of 83% for a second visit despite early enrollment occurring during COVID restrictions. Retention rates for third and fourth visits are even higher (90% and 97% respectively), suggesting a high degree of engagement in longitudinal participants. Including historic data from ARTFL and LEFFTDS, >1000 participants have multiple visits.ConclusionLongitudinal assessment of clinical and biomarker profiles in f‐FTLD and s‐FTLD can inform models of disease onset and progression, allowing analysis of disease trajectories and identification of the most sensitive clinical outcome measures over time. ALLFTD has been successful at recruiting and retaining a large active cohort to obtain detailed clinical and biomarker characterizations; data are available by request.

AbstractBackgroundSex differences in neurodegenerative diseases can impact accurate diagnosis and management. Emerging data suggest there may be sex differences in frontotemporal dementia (FTD) prevalence and clinical manifestation. However, prior studies lacked longitudinal assessment and were limited in capturing sex differences in earliest stages of disease (e.g., preclinical). We evaluated how sex impacts longitudinal clinical outcomes in individuals carrying autosomal dominant variants for FTD.Method337 participants carrying pathogenic variants in MAPT, GRN, or C9orf72 completed longitudinal evaluations (2.4 average visits, range = 1‐6), including neuropsychological and functional assessments, and plasma analyzed for neurofilament light chain (NfL). FTLD Clinical Dementia Rating Scale (FTLD‐CDR) classified disease stage at study entry (FTLD‐CDR = 0: asymptomatic; FTLD‐CDR = 0.5: MCI; FTLD‐CDR> 0.5: Dementia). Linear mixed‐effects models evaluated the effect of sex on longitudinal clinical trajectories, including the effect of disease stage at study entry.ResultMale and female carriers were similarly distributed with respect to baseline demographics and most clinical outcomes. However, women exhibited higher baseline NfL than men. Not accounting for disease stage, men and women did not show statistical differences on cognitive, functional, or NfL trajectories. However, when accounting for disease stage, there was a significant interaction between baseline disease stage, sex, and time on cognitive, NfL, and functional trajectories. While sex differences were not statistically significant among asymptomatic carriers, women with MCI/dementia evidenced more rapid cognitive, NfL and functional decline over time compared to men. To evaluate the role of pathology burden, we tested the interaction between baseline NfL, sex, and time on clinical outcomes stratified by disease stage. In asymptomatic participants, women showed an attenuated adverse relationship between baseline NfL and clinical trajectories compared to men. No statistically significant sex differences were evident in the relationship between baseline NfL and clinical outcomes in participants with MCI/dementia.ConclusionIn familial FTD, women evidenced steeper clinical declines than men after symptom onset. Accounting for pathology, baseline NfL was a stronger predictor of clinical decline in asymptomatic men compared to women. NfL may be a less sensitive prognostic tool for clinical progression in women with FTD, particularly early in disease. This may reflect early “cognitive resilience” to neurodegeneration in women.

AbstractBackgroundFrontotemporal dementia (FTD) is a diverse spectrum of neurodegenerative disorders impacting the frontal and temporal lobes, primarily manifesting as behavioral and/or language issues. Accurate diagnosis is crucial for effective management, potential treatment, and care planning. While speech analysis has shown promise in detecting cognitive markers of Alzheimer’s disease (AD), its exploration in FTD is limited. This study examined if linguistic features from remote, app‐based speech collection can differentiate healthy controls (HC) from individuals with behavioral variant FTD (bvFTD), the most common FTD variant.MethodParticipants included 15 bvFTD (mean age = 64.3, SD = 9.1 years) and 19 HC (mean = 55.8, SD = 14.2) from the ALLFTD Consortium. Participants were prompted to talk freely about a happy memory; audio recordings were collected with the ALLFTD Mobile App, transcribed using OpenAI’s large Whisper model, and manually quality‐checked. We extracted 98 linguistic features using our in‐house pipeline (Fig 1). Features were selected for classification analysis if they differed between groups based on a MANCOVA adjusted for age, sex/gender, and education, with feature reduction in case of collinearity. We then determined if these features could classify groups using multi‐variable logistic regression models, and subsequently calculated its ROC‐AUC score to measure sensitivity/specificity.ResultBased on the MANCOVA, three features were selected for classification analysis: average seconds of non‐speech (i.e., silence), ratio of number of complex nominal clauses to total clauses, and number of restarts (i.e., disfluency). The logistic model showed that this set could distinguish between groups (Omnibus p = .001; Nagelkerke R2 = .499), and their saved prediction probabilities indicated a ROC‐AUC score of 84.8% accuracy (Fig 2).ConclusionLeveraging a flexible speech capture app with remote accessibility and state‐of‐the‐art automated speech analysis, we identified linguistic features that can distinguish HC from bvFTD. This approach presents a promising screening tool for detecting bvFTD, offering quick, easily administered assessments with the potential for scalable implementation outside of clinical settings. Next steps are to investigate linguistic changes in presymptomatic mutation carriers and compare speech profiles between FTD and AD. These results hold meaningful implications for addressing current challenges in FTD therapeutics, potentially offering sensitive outcome measures for clinical trials and future tools for personalized cognitive assessment and long‐term monitoring.

AbstractBackgroundFrontotemporal dementia (FTD) is a common young‐onset dementia. Challenges to in‐person FTD evaluations (e.g., behavioral symptoms, disease rarity), highlight the need to develop remote, low‐burden assessment techniques. A growing literature supports passive digital phenotyping for monitoring neurobehavioral change. Thus, we examined the utility of passively collected data from smartphones to detect prodromal or symptomatic FTD compared to that of the Montreal Cognitive Assessment (MoCA), a common cognitive screener.Method199 adults enrolled in the ALLFTD Mobile App study (mean age = 53.4 [SD = 15.2]; 58% women) completed up to 6 months of passive smartphone monitoring via the ALLFTD Mobile App. 55% were unimpaired [CDR®+NACC FTLD = 0], 22% had prodromal FTD [CDR®+NACC FTLD = 0.5], and 23% had symptomatic FTD [CDR®+NACC FTLD≥1] with a variety of syndromic presentations. Battery percentage was collected frequently (median interval = 45 min), and total daily battery usage was calculated as a proxy for smartphone use (higher battery usage = more smartphone use). Daily step counts were also passively collected. Logistic regression classified prodromal or symptomatic FTD vs. unimpaired as a function of: MoCA score [Model 1]; 7 passive features characterizing average, inter‐day variability, and changes over time in smartphone use and movement [Model 2]; or passive smartphone features and MoCA [Model 3]. Analyses were repeated excluding participants with symptomatic FTD to detect prodromal FTD vs. unimpaired.ResultThe area under the curves (AUCs) for detecting prodromal or symptomatic FTD (vs. unimpaired) from the MoCA alone [Model 1] and passive smartphone features alone [Model 2] were 0.77 (95%CI: 0.70‐0.85) and 0.77 (95%CI: 0.70‐0.84), respectively. Their combination [Model 3] resulted in a significantly improved AUC of 0.86 (95%CI: 0.80‐0.92) compared to Model 1 (p = 0.001). Significant Model 3 predictors included average daily battery usage (p = 0.02), slopes of change in step count (p = 0.04), and MoCA score (p<0.01). When distinguishing prodromal FTD from unimpaired, passive smartphone features alone (AUC = 0.75) were significantly better than the MoCA alone (AUC = 0.66; p<0.01), and their combination had the largest AUC (0.80).ConclusionResults support the utility of novel passively collected information from smartphones for detecting and monitoring FTD without contributing to assessment burden. With continued validation, passive digital monitoring methodologies have potential to increase access to dementia care.

Abstract INTRODUCTION Psychotropic medication (PM) use in behavioral‐variant frontotemporal dementia (bvFTD) is higher than in other dementias. However, no information exists on whether PM use differs between sporadic and genetic bvFTD. METHODS We analyzed data from sporadic and genetic bvFTD participants with PM prescriptions in the Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects study. We estimated ordinal odds ratio (OOR) of having more PM comparing sporadic and genetic bvFTD. Finally, we explored the neuropsychiatric symptom (NPS) combinations using classification and regression trees (CART). RESULTS We included 263 with sporadic and 193 with genetic bvFTD. The OOR for sporadic bvFTD to be on PM was 1.75 (95% confidence interval: 1.21 to 2.53) for the fully adjusted model. CART revealed the most common NPS combination was apathy + personality changes in 18% of participants. DISCUSSION Participants with sporadic bvFTD were twice as likely to be on PM compared to genetic bvFTD. The reason for increased PM usage in sporadic bvFTD participants should be further investigated. Highlights We report on patients with behavioral variant frontotemporal dementia (bvFTD). We evaluated the psychotropic medication (PM) prescription at baseline in the cohort. Patients with sporadic bvFTD had more prescriptions for PM than genetic patients. The frequency of symptoms combination was different in sporadic and genetic bvFTD.