Citations

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.

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.

Portopulmonary hypertension (POPH), a form of pulmonary artery hypertension, occurs because of portal hypertension. Pulmonary hemodynamics and right heart function are key entities that are considered when diagnosing and treating POPH. Medical management, combined with liver transplantation, offers a unique opportunity for POPH “cure”; however, transplant risk can be significant as it relates to the severity of POPH. In addition to recent POPH practice guidelines, continued efforts can be suggested to improve our understanding of prognostic factors, investigate newer medical treatments, and improve outcomes of POPH. Herein, we identify specific “unmet needs” that focus on expanding and complementing current POPH practice guidelines.

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.

Background Underserved patient populations characterized by low income, lack of insurance, low levels of education, and minoritized status face significant barriers when accessing clinical trials. To better understand these challenges, patients from a safety-net county hospital were surveyed on their perspectives on clinical trials, barriers to care, and facilitators of participation. Methods Patients ≥ 18 years old with histologically confirmed non-Hodgkin lymphoma (NHL) who received care at Lyndon B. Johnson Hospital, a safety-net county hospital in Houston, Texas, were invited to participate regardless of treatment status. A self-administered questionnaire was used and offered in English or Spanish. The questionnaire included a total of 53 items with an additional 13 demographic items assessing patient sociodemographic factors and knowledge of clinical trials. Questions also addressed barriers/facilitators of trial participation and respondent willingness to participate in a trial based on certain scenarios. Results Of the 136 patients invited to participate, a total of 49 participants diagnosed with NHL consented to the study and all completed the survey (participation rate 36%). Twenty-seven (55%) surveys were completed in Spanish. Participants self-identified as Hispanic (N=35, 71.4%), African American (N=6, 12.2%), non-Hispanic white (N=7, 14.3%), and Asian/Pacific Islander (N=1, 2%). This cohort included Diffuse Large B-cell lymphoma NOS (DLBCL) [32%], Follicular Lymphoma (FL) [28%], Marginal Zone lymphoma (12%). There were several patients with rare histologies such as Burkitt's lymphoma (4.2%); Mantle Cell lymphoma (4.2%), Plasmablastic lymphoma (4.2%) and T-cell lymphoma (4.1%). The majority of participants reported a commute of less than an hour away to the doctor's office (83%) with almost all participants commuting less than 2 hours (98% with 2% missing an answer). Participants were a median age of 55 years old (range 22-80), majority female (51%), less than a bachelor's degree as highest education (91.8%) and earning &lt; $35,000 (49%). Among respondents, 89.8% had not participated in a clinical trial for their cancer. Only 36.7% of respondents reported that they understood what a clinical research study as “somewhat well,” while 30.6% reported their understanding as “not very well.” Regardless, a majority were very willing (38.8%) or somewhat willing (36.7%) to participate in a trial as their initial course of treatment. Respondents' biggest concerns were the cost of a clinical trial (61.2%), not being able to contact the research team with questions (38.8%), and frequency of clinic visits (32.7%). The most helpful resources that participants identified to reduce participation burden were educational resources such as written materials (77.6%), videos (67.3%), an explanation of the study in their language (65.3%), insurance aid (75.5%), and flexible study visit times (65.3%). Notably, 26.5% of participants responded that they believed they had received medication from a doctor as part of an experiment without their permission. When asked which outcome would most influence their decision to participate in a trial, 79.6% of participants rated the possibility of improving quality of life by decreasing pain and increasing activity levels as very important. Fewer patients (55%) rated other outcomes such as types of side effects (55%) and possibility of pain/discomfort (59%) as very important. Conclusions The majority of patients with NHL who participated in this observational study had little or no previous exposure to or understanding of cancer clinical trials. We identified common barriers to participation including out-of-pocket costs, the ability to contact the research team, and the frequency of clinic visits that should be addressed with specific identified resources to reduce participation burden. Interventions guided by these data should be implemented and evaluated to improve clinical trial participation for patients with lymphoma.

AbstractBackgroundAccurately estimating glomerular filtration rate (GFR) is crucial for dosing medications in hospitalized patients. Due to limitations of serum creatinine for GFR estimation, serum cystatin C (CysC) has been explored as an alternative functional kidney biomarker. This study assessed discordance between eGFRCr and eGFRCysC in a large sample of hospitalized patients and examined the frequency of renally eliminated medications affected by eGFR discordance.MethodsThis multisite historical study included adults hospitalized between 2011 and 2023 with CysC and serum creatinine reported within 24 h of each other. The first concurrent biomarker pair for each patient was analyzed. eGFR discordance and use of renally eliminated medications were described.Results17,718 hospitalized patients with concurrent creatinine and CysC assessments were included. The median eGFRCr was 65 mL/min, and the eGFRCysC was 46 mL/min. The median absolute difference of eGFRCr−eGFRCysC was 15 mL/min, and 7972 patients (45%) had a > 30% absolute difference. There was a significantly greater percentage of patients with an eGFR <30 mL/min based on eGFRCysC (26%) compared to eGFRCr (15%) (p < 0.001). Patients were prescribed an average of 20 medications in the 24 h surrounding the concurrent biomarker assessment. Renally eliminated medications accounted for 39% ± 13% of medication orders, and 80% of patients with eGFR discordance were prescribed five or more renally eliminated medications.ConclusionSubstantial eGFR discordance between eGFRCysC and eGFRCr was observed in hospitalized patients, which directly affects the dosing of renally eliminated medications. Further research is needed to optimize the pharmacotherapy of renally eliminated medications with discordant GFR assessments to improve medication safety and effectiveness.