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Background Inhaled treprostinil (iTre) is the only treatment approved for pulmonary hypertension due to interstitial lung disease (PH-ILD) to improve exercise capacity. This post hoc analysis evaluated clinical worsening and PH-ILD exacerbations from the 16-week INCREASE study and change in 6-minute walking distance (6MWD) in the INCREASE open-label extension (OLE) in patients with less severe haemodynamics. Methods Patients were stratified by baseline pulmonary vascular resistance (PVR) of <4 Wood units (WU) versus ≥4 WU and ≤5 WU versus >5 WU. Exacerbations of underlying lung disease, clinical worsening and change in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in INCREASE were evaluated. For the OLE, patients previously assigned to placebo were considered to have a 16-week treatment delay. 6MWD and clinical events in the OLE were evaluated by PVR subgroup. Results Of the 326 patients enrolled in INCREASE, patients with less severe haemodynamics receiving iTre had fewer exacerbations of underlying lung disease and clinical worsening events. This was supported by the Bayesian analysis of the risk of disease progression (HR<1), and significant decreases in NT-proBNP levels. In the OLE, patients without a treatment delay had improved exercise capacity after 1-year compared with those with a 16-week treatment delay (22.1 m vs −10.3 m). Patients with a PVR of ≤5 WU without a treatment delay had a change of 5.5 m compared with −8.2 m for those with a treatment delay. Patients without a treatment delay had a prolonged time to hospitalisation, lung disease exacerbation and death. Conclusion Treatment with iTre led to consistent benefits in clinical outcomes in patients with PH-ILD and less severe haemodynamics. Earlier treatment in less severe PH-ILD may lead to better exercise capacity long-term, however, the subgroup analyses in this post hoc study were underpowered and confirmation of these findings is needed.

Background. Portopulmonary hypertension (PoPH) occurs in patients with advanced liver disease and can be a contraindication to liver transplant (LT). Improvement of hemodynamic parameters with pulmonary arterial hypertension (PAH) therapies (including endothelin receptor antagonists [ERAs]) may help some patients to become eligible for LT. Methods. We conducted a retrospective secondary data analysis to describe the clinical course and management of PoPH in patients on a US registry LT waitlist and outcomes in patients receiving an ERA. Results. At the time of LT waitlist entry (1996–2019), patient characteristics and disease severity were similar in the 685 patients with PoPH enrolled overall (LT waitlist data set) and the 420 of them who underwent LT (LT data set). Most patients (92.0%) had a model for end-stage liver disease exception granted before entering the LT waitlist. Patients spent a median of 8.9 mo (interquartile range, 3.7–19.7) on the LT waitlist before undergoing LT. Overall, 77.1% of patients received PAH treatment at LT waitlist entry (ERAs, 30.1%). Hemodynamic parameters improved in ≥95% of patients between the first assessment versus the second (median interval, 9 mo) and last assessments (median interval, 14 mo). At the first assessment, 49.6% of patients had mean pulmonary arterial pressure ≥45 mm Hg versus 2.6% and 1.8% of patients at the second and last assessments, respectively; 47.5% of patients had pulmonary vascular resistance >450 dynes·s/cm5 versus 0.9% and 0.2% of patients at the second and last assessments. One-year survival was 90.6% (95% confidence interval [CI], 87.6-92.9) following LT waitlist entry and was 86.4% (95% CI, 82.6-89.5) after LT; 5-y survival was 67.4% (95% CI, 60.0-73.8) while on the LT waitlist (before LT) and was 75.6% (95% CI, 70.4-80.0) following LT. Conclusions. This large US study of patients with PoPH on an LT waitlist confirms that effective PAH treatments can help patients achieve acceptable hemodynamics, providing the opportunity to undergo LT.

AbstractPulmonary hypertension (PH) associated with chronic kidney disease (CKD) (PH‐CKD) affects approximately 20%–40% of CKD patients and is associated with increased morbidity and mortality. PH and CKD are both pathophysiologically associated with nitric oxide (NO) deficiency. The NO pathway, an important therapeutic domain in pulmonary arterial hypertension (PAH), is an intriguing but unexplored target in PH‐CKD. We sought to improve understanding of the clinical significance of the NO pathway in patients with PH‐CKD by assessing the hemodynamic response to inhaled NO (iNO) during right heart catheterization (RHC). In this retrospective cohort study, patients with diagnosis codes of PH and stage IV/V CKD or end‐stage renal disease and estimated glomerular filtration rate < 60 mL/min/body surface area who underwent RHC and hemodynamic drug study between July 2011 and June 2021 were eligible. Patients with mean pulmonary artery pressure (mPAP) > 20 mmHg and pulmonary vascular resistance (PVR) > 3 Wood units were included. The final cohort included 37 patients (45.9% female, mean age 72.5 ± 9.7 years). A total of 56.7% of the cohort (21/37) had precapillary PH, while 43.2% (16/37) had combined precapillary postcapillary PH (Cpc‐PH). Median survival was 3.1 years after RHC. iNO was associated with a significant decrease in both mPAP and PVR. Hemodynamic changes in mPAP and PVR were similar in precapillary and Cpc‐PH groups. Among a small subset (n = 14) who were subsequently treated with PAH‐targeted therapy, treatment response was mixed and did not reveal significant benefit. Further studies are warranted to better define the potential role of PAH therapy in PH‐CKD.

AbstractChronic lung disease (CLD) is the second leading cause of pulmonary hypertension (PH) and is associated with significant morbidity and mortality. Although PH associated with CLD (PH‐CLD) leads to impaired health‐related quality of life (HRQOL), there are no validated tools to assess HRQOL in PH‐CLD. The Pulmonary Arterial Hypertension–Symptoms and Impact Questionnaire (PAH‐SYMPACT) is an HRQOL instrument aimed at assessing the symptoms and impact of PH on overall function and well‐being. We performed a single‐center prospective cohort study using PAH‐SYMPACT scores to compare symptoms, exercise capacity and HRQOL in patients with PAH and PH‐CLD. One hundred and twenty‐five patients (99 patients with idiopathic/heritable PAH and 26 with PH‐CLD) completed the PAH‐SYMPACT questionnaire which consists of 22 questions that assess HRQOL across four domains: cardiopulmonary (CP) symptoms, cardiovascular (CV) symptoms, physical impact (PI), and cognitive/emotional (CE) impact. Higher scores indicate worse HRQOL. We compared patients with PAH and PH‐CLD using a Wilcoxon rank sum or chi‐squared test as appropriate. Multivariate linear regression analysis was used to assess the relationship between PH classification and SYMPACT scores. Compared to PAH, patients with PH‐CLD were older, more likely to use oxygen and had worse functional class and exercise capacity. While there was no significant difference between the two groups in CP, CV, or CE domain scores, patients with PH‐CLD had significantly worse PI scores by univariate (1.79 vs. 1.13, p < 0.001) and multivariate analysis (1.61 vs. 1.17, p = 0.02) and overall worse SYMPACT scores (1.19 vs. 0.91, p = 0.03). In conclusion, patients with PH‐CLD have worse HRQOL as assessed by the PAH‐SYMPACT questionnaire versus patients with PAH. Although PAH‐SYMPACT has not been validated in PH‐CLD, the results of this study can guide clinicians in understanding the symptoms and impact of PH‐CLD relative to PAH.

AbstractPulmonary rehabilitation (PR) is a supervised exercise program for patients with chronic lung disease. Among patients with pulmonary hypertension (PH), PR has been shown to improve both quality of life and exercise capacity. The purpose of this study was to assess the prevalence of PR participation among PH patients, patient perspectives regarding PR, and to identify potential barriers to PR participation. We performed a cross‐sectional survey of patients with self‐reported PH who attended the Pulmonary Hypertension Association (PHA) conference in June 2022 in Atlanta, Georgia, and patients within the PHA listserv. A total of 429 participants completed the survey and were enrolled in the study. The average age of participants was 61 ± 14 years with 83% of participants identifying as female, 51% of patients self‐reported as having group 1 PH. Among patients who completed the survey, 41% had previously attended a PR program. Of those who had completed a PR program, 83% reported being satisfied or very satisfied with the program and 86% reported that they would recommend PR to other PH patients. After completion of a PR program, 76% of patients reported an improvement in their quality of life and 88% reported improvement in exercise capacity. Among the patients who had not previously participated in PR (n = 254), 63% reported an interest in participation while 64% cited a lack of discussion from their treatment team as the primary reason for the lack of PR participation. Limitations of the study include sampling and response bias. According to this cross‐sectional survey, the majority of PH patients who have participated in PR report improvement in both quality of life and exercise capacity and would recommend PR to other PH patients. The majority of PH patients who have not participated in PR were interested in participation and cited a lack of discussion with their treatment team as one of the primary reasons for the lack of participation. PR is associated with self‐reported improvements in quality of life and exercise capacity but remains underutilized among patients with PH.

AbstractBackgroundThe rural‐urban commuting area (RUCA) codes classify communities using measures of population density, urbanization, and daily commuting from U.S. Census Bureau information. The ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study generated RUCA codes for enrolled participants to better understand our cohort demographics. The rural‐urban distribution of participants may provide important insights for clinical trial planning.MethodsThe current RUCA codes are generated from the 2010 decennial census and the 2006‐10 American Community Survey data. The codes are numbers (1‐10) that describe metropolitan, micropolitan, small town, and rural commuting areas based on the size and direction of the primary (largest) commuting flows.ResultsRUCA codes were generated on 784 ALLFTD participants. At their most recent visit, participant median age was 60, 51.1% female, and a median education of 16 years. Participants were classified as clinically normal (39.1%), behavioral variant FTD (25%), nonfluent PPA (6.7%), semantic variant PPA (6.6%), PSP (4.7%), MBCI (4.8%), corticobasal syndrome (5.9%), and the remaining 7% of participants had other dementia‐related diagnoses. For participants with sporadic disease, 87.4% live in a metropolitan area, 6.7% a micropolitan area, 3.2% a small‐town area, and 3.2% live in a rural area. In familial FTLD, a larger percentage of participants live in micropolitan or small town/rural community (18.8% combined; p = 0.029), driven largely by MAPT family participants (n = 101). 10% of those with a familial MAPT mutation live in a rural area; with an additional 18% in micropolitan (12.9%) or small‐town areas (5%). Among those with a familial C9orf72 expansion, 83.3% live in a metropolitan area, 8.9% micropolitan area, 5.6% in a small‐town area, and 2.2% in a rural area. Participants with a familial GRN mutation show a similar distribution: 84.7% live in a metropolitan area, 5.6% micropolitan, 6.9% small‐town, 2.8% rural.ConclusionsAdditional analyses to better understand if FTD families are disproportionately living in rural communities are underway. These analyses will better characterize sporadic and familial FTD demographics to assist with clinical trial design.

AbstractBackgroundCardiovascular health plays an important role in brain aging; yet its role in development of autosomal dominant forms of dementia and frontotemporal dementia (FTD) has not been fully elucidated. Life’s Simple 7 (LS7) is a metric of cardiovascular health associated with reduced dementia risk and may represent a transdiagnostic heuristic to promote brain health. We examined the extent to which baseline LS7 associated with cognitive and brain aging trajectories in individuals with genetic FTD.Method243 adults carrying autosomal dominant genetic mutations for FTD and 189 non‐carriers completed neuroimaging, neuropsychological testing, and medical interviews. LS7 at baseline was computed following established procedures based on physical activity, diet, body mass index, smoking, hypertension, diabetes, and hypercholesterolemia; higher scores indicate more optimal cardiovascular health. We examined interactions between baseline LS7 and mutation carrier status on cognitive and brain structural outcomes at baseline (via linear regression) and longitudinally (via linear mixed‐effects models). All models adjusted for baseline age, sex, and education, and CDR®+NACC FTLD.ResultMutation carriers and non‐carriers did not significantly differ on baseline LS7 (t = ‐1.42, p = 0.156). At baseline, there were significant interactions between LS7 and carrier status on frontotemporal (FTL) volume and executive functioning (all p‐values<0.046), such that positive associations between LS7 and neurobehavioral outcomes were stronger among mutation carriers versus noncarriers. Longitudinally, there was also a significant interaction between carrier status and baseline LS7 on memory over time (b = 0.04,p = 0.035) and the interaction approached significance for language trajectories (b = 0.03,p = 0.079); again, the association between higher LS7 and slower cognitive decline was stronger among mutation carriers versus noncarriers, even when excluding symptomatic carriers (b = 0.04,p = 0.047). Among mutation carriers only, higher baseline LS7 related to slower memory (b = 0.04,p = 0.006) and language declines over time (b = 0.044,p = 0.004), but did not significantly relate to FTL volume (b = ‐0.01,p = 0.307) or executive functioning trajectories (b = 0.004,p = 0.913)ConclusionBetter cardiovascular health relates to larger baseline frontotemporal volume and slower cognitive decline in individuals with autosomal dominant FTD. Interaction models suggested the degree to which cardiovascular health associates with better neurobehavioral outcomes is stronger in mutation carriers. Optimizing cardiovascular health may be a particularly important, modifiable approach to mitigate the symptoms associated with pathogenic variants of FTD.

Abstract Background The ALLFTD (ARTFL‐LEFFTDS Longitudinal Frontemporal 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. ALLFTD represents the merger and continuation of two prior studies: Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Methods ALLFTD recruits participants with FTLD spectrum disorders (bvFTD, svPPA, nfvPPA, FTD‐ALS, CBS or PSP), with strong family histories of FTLD, or known FTLD‐associated genetic variants within the family. 26 sites in North America enroll participants for clinical and neuropsychological evaluations, MR Imaging, blood draws, and CSF collection in willing participants; participants are requested to return annually for follow‐up evaluation. All participants are genotyped for dementia‐associated mutations. Participants also enroll in the FTD Disorders Registry for follow‐up surveys. A subset of participants undergo remote assessment via the ALLFTD app. Visits conducted under ARTFL and LEFFTDS are included in the ALLFTD dataset. Results ALLFTD has been successful in developing methods to conduct remote or hybrid visits and in actively evaluating participants. Since ALLFTD began in January 2020, 1034 participants (736 new; 298 previously enrolled in ARTFL or LEFFTDS) have been evaluated in the longitudinal arm; an additional 119 participants have been participated in a shortened, biofluid‐focused visit. 349 have returned for follow‐up visits. Including prior participants, the ALLFTD dataset contains 3871 visits from 2343 individuals. 1277 people have sporadic syndromes; 1045 were enrolled as familial. Among s‐FTLD, bvFTD is the most common phenotype (32.8%) followed by PSP (15.9%). 61.4% of f‐FTLD participants were clinically normal at first visit; bvFTD is the most common syndrome in symptomatic f‐FTLD (40%). 477 are confirmed carriers of FTLD‐associated genetic mutations. MRIs were obtained for 2594 visits; 3492 visits have associated blood biospecimens banked; 978 visits have associated CSF samples. Conclusions The ALLFTD consortium is actively evaluating participants across North America to better characterize FTLD syndromes and support the planning and development of FTLD clinical trials. Longitudinal datasets including clinical, genetic, and imaging data are available by request.

AbstractBackgroundFrontotemporal Dementia (FTD) patients are geographically dispersed and often have behavioral and/or motor deficits that limit access to in‐person clinical trials and research. To address these participation barriers, we investigated the feasibility of installing in‐home sensor technologies to remotely assess everyday functioning in FTD.MethodWe aimed to recruit 20 FTD participants with a variety of clinical syndromes, including behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP). We also aimed to enroll a study partner for each participant that lived in the same home to serve as a control. The Collaborative Aging Research Using Technology (CART) platform was installed in participants’ homes to collect continuous data for up to two years, using motion sensors, physiological monitoring devices (e.g., scales, sleep sensors), electronic pillboxes, and wearable actigraphs. Computer use and driving patterns were also tracked. Technology was installed either via a study coordinator visit or remotely through video and written instructions, based on schedule and logistics. Participants were asked to complete a weekly Qualtrics survey about time away from home, visitors, and health changes.ResultOf the 159 UCSF participants available for recruitment through ALLFTD and other FTD projects, 28% (N = 45) met inclusion criteria. Of those 45, ten were ineligible due to advanced disease severity or relocation to an assisted living facility. A third (36%, N = 17) declined due to overwhelmed study partners (N = 3), declined any subproject participation (N = 7), sensitivity to participant’s diagnosis (N = 2), or lack of response (N = 5). Two additional participants were recruited through UCLA’s ALLFTD cohort. The platform has been installed in 19 homes (bvFTD: n = 10; PPA: n = 5; CBS/PSP: n = 4). Two homes discontinued due to death or relocation to assisted living facility. Mean data collection is 360 days (max = 527). Of 103 reported technological issues, 92% were resolved without additional home visits, either by phone or email. Participants completed 65% of weekly health questionnaires.ConclusionsAlthough there were some recruitment and retention challenges, these findings generally provide preliminary support for the feasibility and sustainability of conducting comprehensive in‐home passive data research in FTD.

AbstractBackgroundThere has been a rise in remote cognitive testing for neurodegenerative diseases. The ALLFTD Mobile App is designed to capture clinical features of frontotemporal dementia (FTD) through repeated remote assessment on smartphones. This is a departure from traditional neuropsychological practice in which a single examiner‐led assessment occurs in a controlled setting. When participants complete tasks on their own, those with greater disease severity may be more variable in their performance for a variety of reasons (e.g. greater distractibility, less engagement). Here we study whether intraindividual cognitive variability (IIV) is associated with older age and increasing disease severity.MethodParticipants were 279 (mean age = 54.9) healthy controls and participants with sporadic FTD or from familial FTD kindreds with a range of disease severities based on FTLD Clinical Dementia Rating scale (CDR®+NACC‐FTLD Global) scores: 0 (n = 132), 0.5 (n = 54), and ≥1 (n = 47). Participants completed three cognitive tasks at least two times across twelve days. Measures included an adaptive memory task and gamified versions of Flanker and Go/no‐go tasks. IIV was operationalized as the standard deviation in performance on each task. Regression analyses investigated the relationship of IIV with CDR®+NACC‐FTLD group, and with age in those without symptoms. Education and gender were included as covariates in all analyses.ResultGreater disease severity (CDR®+NACC‐FTLD) was associated with greater variability on Flanker (p<.001) and Go/No‐go (p = .02) tasks; a positive but non‐significant association was seen with memory testing (p = .16). Post‐hoc comparisons found that those with CDR®+NACC‐FTLD of 0.5 had significantly more IIV on the Flanker task (𝛃 = .39, p = .004) than those with CDR®+NACC‐FTLD’s of 0. Moreover, those with a CDR®+NACC‐FTLD ≥1 had significantly greater IIV on the Flanker (𝛃 = .85, p<.001) and Go/No‐go tasks (𝛃 = .51, p = .007) than those with a CDR®+NACC‐FTLD of 0. In those without symptoms (CDR®+NACC‐FTLD = 0), age was associated with increased IIV on the Flanker (𝛃 = .27, p<.001) and Go/no‐go (𝛃 = .23, p<.001) tasks.ConclusionIncreased IIV, particularly on processing speed/executive functioning tasks, was associated with greater age and greater functional impairment, even in the mildest stages. Future investigations exploring predictors of IIV and the prognostic value of IIV are warranted.