Citations

AbstractBackgroundAutonomic dysfunction has been linked to empathy deficits in symptomatic frontotemporal degeneration (FTD), but less is known about pre‐symptomatic FTD mutation carriers (preFTD+). Our prior work found that increasing resting heart rate (RHR) over time predicts decline in emotional empathy in preFTD+. Here, we replicate previous findings in a large, multi‐site consortium sample and assess relationships between RHR and empathy loss across disease stages.MethodRHR and Interpersonal Reactivity Index (IRI) were obtained serially for up to 7 years in 348 preFTD+, 202 symptomatic FTD mutation carriers (FTD+), and 311 non‐carrier family members (FTD‐) enrolled in ALLFTD. IRI Perspective Taking (IRI‐PT) and Empathic Concern (IRI‐EC) subscales measured cognitive and emotional empathy, respectively. Separate multiple linear regressions related mutation status and annualized change in RHR to annualized change in IRI subscales and assessed interactions between RHR change and phenoconversion status among mutation carriers. Logistic regression was used to assess the association between change in RHR and phenoconversion among mutation carriers, and Wilcoxon signed‐rank tests were used to examine differences in change in RHR between all study groups.ResultIn asymptomatic participants (preFTD+ and FTD‐), increase in RHR over time was associated with greater decline in IRI‐EC (ß = ‐0.07, p<.001) and IRI‐PT (ß = ‐0.03, p = .011), regardless of mutation status. Among mutation carriers (preFTD+ and FTD+), increase in RHR was associated with greater decline in IRI‐EC (ß = ‐0.04, p = .041), and this effect was stronger in FTD+ compared to PreFTD+ (ß = ‐0.07, p = .038), while an increase in RHR was associated with decline in IRI‐PT only in FTD+ (ß = ‐0.07, p = .046). Change in RHR did not predict phenoconversion in mutation carriers (PreFTD+ and FTD+), but PreFTD+ showed less change in RHR over time relative to FTD+.ConclusionChanges in empathy in asymptomatic preFTD+ and FTD‐ are linked to variability in RHR regardless of genetic status, likely reflecting a non‐specific impact of autonomic functioning on empathy and prosocial behavior. In contrast, increasing RHR predicts decline in cognitive and emotional empathy in FTD mutation carriers but primarily after phenoconversion, suggesting that autonomic contributions to empathy in familial FTD increase with disease progression and could be an early marker of manifest disease.

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.

AbstractBackgroundFrontotemporal dementia (FTD) presents with heterogeneous neuropsychiatric symptoms (NPS). These symptoms often begin prior to the onset of FTD, and progress throughout the prodromal stages of FTD. Particularly, familial FTD due to autosomal dominant genetic mutations might display mutation‐specific NPS profiles. We hypothesized distinct NPS trajectories for chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule‐associated protein tau (MAPT) mutation carriers during their transition from presymptomatic to symptomatic stages of FTD.MethodIn this study, we analyzed N = 1662 participants from the ARTFL‐LEFFTDS Longitudinal FTLD (ALLFTD) Study, with 342 C9orf72, 148 GRN, 168 MAPT mutation carriers, and 1004 noncarriers. We used the CDR plus NACC FTLD global scores to define the conversion status, and stratified participants into four stages of progression: 1) Presymptomatic (CDR = 0 throughout the follow‐up), 2) Early conversion (began with CDR = 0, then increased to 0.5), 3) Advanced conversion (began with CDR = 0.5, then increased to 1.0 or above), and 4) Symptomatic (CDR>1.0 throughout). Over up to seven visits, the Neuropsychiatric Inventory Questionnaire (NPI‐Q) assessed changes in NPS. We analyzed total NPI‐Q score trajectories using a generalized linear mixed‐effects model, adjusting for age and baseline NPI‐Q scores.ResultOur findings showed similar NPS trajectories among carriers and noncarriers during presymptomatic stages. However, in the early conversion stage, C9orf72 and GRN carriers exhibited significantly higher NPI‐Q score increases compared to MAPT carriers, primarily in the psychosis and hyperactivity domains. In the advanced and symptomatic stages, the rate of increase in NPS was not significantly different across groups.ConclusionThis study suggests that people with familial FTD, particularly those predicted to have underlying TDP‐43 pathology, may experience more severe neuropsychiatric symptoms like psychosis or hyperactivity as they progress from presymptomatic to prodromal phases. This trajectory appears distinct from those with tau pathology or sporadic FTD. Further studies are warranted to understand these unique progression patterns and their implications for FTD management.

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.

AbstractThe tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies. In this context, designing the most efficient development programs to translate promising targets and treatments from preclinical studies to early‐phase clinical trials is vital. In September 2022, the Rainwater Charitable Foundation convened an international expert workshop focused on the translation of tauopathy therapeutics through early‐phase trials. Our report on the workshop recommends a framework for principled drug development and a companion lexicon to facilitate communication focusing on reproducibility and achieving common elements. Topics include the selection of targets, drugs, biomarkers, participants, and study designs. The maturation of pharmacodynamic biomarkers to demonstrate target engagement and surrogate disease biomarkers is a crucial unmet need.Highlights Experts provided a framework to translate therapeutics (discovery to clinical trials). Experts focused on the “5 Rights” (target, drug, biomarker, participants, trial). Current research on frontotemporal degeneration, progressive supranuclear palsy, and corticobasal syndrome therapeutics includes 32 trials (37% on biologics) Tau therapeutics are being tested in Alzheimer's disease; primary tauopathies have a large unmet need.

AbstractINTRODUCTIONCardiovascular health is important for brain aging, yet its role in the clinical manifestation of autosomal dominant or atypical forms of dementia has not been fully elucidated. We examined relationships between Life's Simple 7 (LS7) and clinical trajectories in individuals with autosomal dominant frontotemporal lobar degeneration (FTLD).METHODSTwo hundred forty‐seven adults carrying FTLD pathogenic genetic variants (53% asymptomatic) and 189 non‐carrier controls completed baseline LS7, and longitudinal neuroimaging and neuropsychological testing.RESULTSAmong variant carriers, higher baseline LS7 is associated with slower accumulation of frontal white matter hyperintensities (WMHs), as well as slower memory and language declines. Higher baseline LS7 associated with larger baseline frontotemporal volume, but not frontotemporal volume trajectories.DISCUSSIONBetter baseline cardiovascular health related to slower cognitive decline and accumulation of frontal WMHs in autosomal dominant FTLD. Optimizing cardiovascular health may be an important modifiable approach to bolster cognitive health and brain integrity in FTLD.Highlights Better cardiovascular health associates with slower cognitive decline in frontotemporal lobar degeneration (FTLD). Lifestyle relates to the accumulation of frontal white matter hyperintensities in FTLD. More optimal cardiovascular health associates with greater baseline frontotemporal lobe volume. Optimized cardiovascular health relates to more favorable outcomes in genetic dementia.