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Abstract Background While type 2 diabetes (T2DM) is a known risk factor for aortic valve calcification (AVC) and aortic stenosis (AS), the specific mechanisms remain unclear. The aim of this study was to determine early factors associated with AVC in patients with T2DM. Methods This cross-sectional study is a pre-specified substudy of an ongoing multicenter randomized controlled trial, the STENO INTEN-CT trial (Screening and Intervention for Subclinical Coronary Artery Disease in Patients With Type 2 Diabetes). Eligibility criteria are patients with diagnosed T2DM without prior ischemic heart disease, and age between 55-69 years (male) and 60-74 years (female). All patients underwent a non-contrast cardiac computed tomography scan and AVC was measured in Agatston units. Results Of the 3635 patients included in this study, nearly half (n = 1694) demonstrated an AVC > 0 (n=1502 with 0 < AVC < 300 and n = 192 with AVC ≥ 300). With increasing AVC, patients were elder, predominantly males, and had significantly more comorbidities (obesity, hypertension, chronic obstructive pulmonary disease, and kidney dysfunction). Patients with higher AVC were more likely to be treated with statins (AVC = 0: n = 1509 (78%), 0 < AVC < 300: n = 1217 (81%), AVC ≥ 300: n = 163 (85%), p = 0.009). Higher body mass index (OR: 1.03 (1.02-1.04), p < 0.001), statin use (OR: 1.49 (1.24-1.80), p <0.001), low-density lipoprotein (OR: 1.24 (1.12 - 1.37), p < 0.001), and kidney dysfunction, measured as urine albumine-creatinine ratio (OR: 1.00 (1.00-1.00), p <0.001), were independently associated with increasing AVC (Figure 1). However, T2DM severity, measured as the duration of T2DM, HbA1c levels, and the number of antidiabetic drugs used, was not associated with increasing AVC severity (Figure 1+2). Conclusion AVC is highly prevalent, affecting nearly half of patients with T2DM. However, early factors driving AVC are not associated with T2DM severity, but rather to diabetes-related comorbidities and complications.

561 Background: For patients with aHCC, second-line treatment options are not well established. The primary aim of this study was to evaluate the efficacy of Futi, an FGFR 1-4 inhibitor, in combination with Pem as a second line therapy in patients with FGF19-expressing aHCC. Methods: Patients aged ≥ 18 years, with histological/cytological diagnosis or radiological diagnosis of HCC, Child-Pugh (CP) class A-B7, Barcelona Clinic Liver Cancer (BCLC) A, B or C, ECOG performance status of 0-2, and FGF19+, by in-situ hybridization or immunohistochemistry, received Futi 20 mg once daily plus i.v. Pem 200mg every 3 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints include overall survival (OS). The study was designed to enroll 22 evaluable patients to detect PFS6 from 25% (historical control) to 47%, assuming a 1-sided alpha of 0.1 with 80% power. All patients provided written consent. Eligible patients with consent who started treatment are considered evaluable. Results: The study was closed to enrollment early at the request of funding agency due to poor accrual. Between 8/2021 and 3/2024, 14 patients enrolled with 1 patient withdrawing consent before beginning protocol treatment. Among 13 evaluable patients, median age was 72 (range: 60-87) years, 7 (53.8%) were male, 12 CP A (92.3%), 7 BCLC C (53.8%), with 7 (53.8%) having received prior liver directed therapy. Median PFS was 15 weeks (95% confidence interval [CI]: 9.0-Not Estimable) and PFS6 was 23.1% (95% CI: 8.6%, 62.3%). Objective response rate was 0% (95% CI: 0%, 24.71%) and stable disease occurred in 7 (53.9%) of patients. Median OS was 55.7 weeks (95% CI: 47.3-NE). Nine (69.2%) patients experienced at least 1 grade 3+ adverse event (AE), and 2 (15.4%) patients experienced at least a grade 4+ AE. One patient had a grade 5 AE unrelated to study treatment (acute kidney injury). Most commonly reported AEs (occurring in more than 31% of patients) were hyperphosphatemia (76.9%), fatigue (69.3%), diarrhea (61.6%), AST (53.9%) and ALT (46.2%), dry eye (38.5%), nail changes (38.5%), rash-maculo-papular (38.5%), and mucositis oral (38.5%). Conclusions: This prospective study evaluated the use of a targeted treatment in combination with immunotherapy following first line immune-based therapy. This combination had modest activity as a second line therapy for patients with aHCC but did not meet the primary endpoint. The safety profile was acceptable and consistent with prior reports. An optimal second-line regimen remains a critical need. Clinical trial information: NCT04828486 .

Abstract INTRODUCTION Tau species lacking truncation of the N‐terminal region, including plasma N‐terminal tau fragment 1 (NT1), have been previously associated with cognitive decline, neurodegeneration, and tau pathology in late‐onset sporadic Alzheimer's disease (AD). METHODS Here, we examined cross‐sectional and longitudinal plasma NT1 as a possible predictor of cognitive, clinical, and core AD biomarker trajectories in autosomal dominant AD (ADAD). RESULTS NT1 levels in ADAD mutation carriers (MC; n = 132) increased across the disease continuum, compared to non‐carriers (NC; n = 75), becoming elevated about a decade prior to estimated symptom onset. Cross‐sectional and longitudinal NT1 levels in MC were associated with clinical, cognitive, and biomarker changes. NT1 increases continued in symptomatic phases of disease, a distinct trajectory from that seen with CSF p‐tau217 and other phospho‐tau species. DISCUSSION Together, our results suggest that plasma NT1—alone or combined with other tau measures—may be useful in studying AD‐related clinical, cognitive, and biomarker outcomes. Highlights Leveraging a deeply phenotyped cohort of individuals carrying a pathogenic variant for autosomal dominant Alzheimer's disease (ADAD) and their non‐carrier family members, our results suggest that plasma N‐terminal tau fragment 1 (NT1) levels mirrored changes in clinical, cognitive, and neurodegenerative measures in ADAD, particularly in late asymptomatic and early symptomatic phases of disease. NT1 levels correlated with cerebrospinal fluid (CSF) measures of tau pathology but less so with CSF or imaging measures of β‐amyloid pathology. Together with previous supportive findings in preclinical and symptomatic sporadic AD, these results suggest that plasma NT1—alone or combined with other tau measures—may be useful in studying AD‐related tau pathology and neurodegeneration across a wide spectrum of disease.

Abstract Background Alzheimer Disease (AD) pathology evolves over decades, and understanding this progression is critical to the understanding of the disease and timing therapeutic interventions. Since individuals with Autosomal Dominant AD (ADAD) develop symptoms around the same age as their parent, it is possible to predict symptom onset and stage individuals by their estimated years to symptom onset (EYO). This approach does not generalize to other forms of AD, thus there is a pressing need for the timecourse of ADAD to be defined in broadly relevant terms. The objective of this project is to validate the Sampled Iterative Local Approximation (SILA) algorithm in a cohort with a known disease timecourse. SILA generates an estimate of time from amyloid positivity (A time ) based on longitudinal PET data. Method We evaluated A time in a longitudinal ADAD sample ( N = 316) with PET PiB data in three ways. First, we compared predicted age at amyloid positive (A+) to observed age at A+ for individuals who became A+ during enrollment. Next, using linear regression, we compared estimated age at A+ to estimated age at symptom onset (EYO=0). Finally, we used generalized additive models to compare the amount of variance in concurrent cognitive performance explained both A time and EYO. Result We observed a mean average error of 1.15 years between actual age at A+ ( N = 26) and the SILA‐predicted A time . Across all participants, SILA‐estimated age at A+ explained 39% of the variance in estimated age at symptom onset ( β = 0.918, p < 0.0001). Finally, we observed a nonlinear association between cognition and both A time and EYO. A time explained 19% of the variance in the general cognitive composite while EYO explained 43% of the variance. Conclusion SILA produces a valid estimate of time‐from‐amyloid positivity in ADAD. This work allows for disease stage in ADAD to be compared to staging for broad forms of AD, which was not previously possible using EYO. However, this work also illustrates that there is a high degree of heterogeneity in preclinical disease duration that is not explained by amyloid alone.

Abstract The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer’s disease to explore the brain asymmetry within the Alzheimer’s disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer’s disease progression in autosomal dominant Alzheimer’s disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.

Abstract Study Objectives Respiratory events during sleep induce immediate cardiac alterations, including increased RR intervals during events and decreased RR intervals after events. However, the extent to which related desaturations and arousals modulate these responses remains underexplored. We hypothesized that desaturations and arousals are the main contributors to respiratory event-related cardiac response, with greatest cardiac alterations expected when both are present. Methods We analyzed RR, QT, and heart rate-corrected QT (QTc) intervals before, during, and after 4310 respiratory events from 129 obstructive sleep apnea patients. Mixed-effect statistical models were utilized to assess the influence of the presence and severity of desaturations and arousals on the cardiac electrical response to respiratory events. Results There were no significant differences between pre- and post-respiratory event RR and QTc intervals in the absence of desaturation or arousal. Arousal (RR estimate = −23.9 ms; QTc estimate = 5.7 ms) or simultaneous desaturation and arousal (RR estimate = −32.8 ms; QTc estimate = 8.4 ms) modulated significantly (p &lt; .05) mean RR and QTc intervals after respiratory events. Desaturation alone affected only RR intervals (estimate = −9.3 ms, p&lt;.05). Greater desaturation depth (RR estimate = −0.09 ms; QTc estimate = 0.56 ms) and longer arousal duration (RR estimate = −3.52 ms; QTc estimate = 0.84 ms) were significant (p &lt; .05) predictors of RR and QTc magnitude alterations after respiratory events. Conclusions Not all respiratory events have the same effects on cardiac electrophysiology; they are associated with acute alterations after events if they cause desaturations and/or arousal, with longer arousal and deeper desaturations increasing the magnitude of cardiac responses. Statement of Significance This study provides a detailed analysis of the temporal dynamics of cardiac response to respiratory events in obstructive sleep apnea patients, with a focus on the potential modulators of this response. Our observations present that not all respiratory events have the same effects on cardiac electrophysiology; they are associated with significant cardiac response if they cause desaturations and/or arousals, with longer arousal and deeper desaturations increasing the magnitude of cardiac response. Our results present evidence of possible modulators of post-event cardiac function, providing a deeper understanding of obstructive sleep apnea’s impact on health as potential underlying mechanisms leading to adverse cardiovascular events.

Abstract DDX3X dysfunction causes an X-linked multisystem disorder with high penetrance and variable expressivity. The phenotypic spectrum spans from learning disability without somatic involvement to profound intellectual disability with severe impairments in the central nervous system and other organs. A few multicenter studies and single case reports have previously highlighted some common phenotypic patterns but were unable to delineate correlations between underlying DDX3X variants and phenotypic findings.From the second largest patient cohort published to date, we analysed clinical, psychometric and diagnostic findings of 52 female and 7 male individuals, harbouring de novo and inherited DDX3X variants. These female patients revealed previously unknown quantitative correlations between variant type and localization and specific phenotypic findings (growth features, epilepsy, brain anomalies, dysmorphisms, motor-focused neurological findings). Moreover, by analysing the in silico folding and RNA binding capability of mutant DDX3X monomers, we were able to delineate novel correlations between DDX3X monomer misfolding grade and phenotypic severity.

Abstract INTRODUCTION Preclinical Alzheimer's disease (AD) can be described relative to biomarker positivity onset time. METHODS We estimated time from amyloid positivity (A+) using sampled iterative local approximation (SILA) in a longitudinal autosomal dominant AD (ADAD) sample ( N = 379) with amyloid positron emission tomography. We compared (1) predicted age at A+ to imputed age, (2) estimated age at A+ to estimated age at symptom onset, and (3) variance in cognitive performance explained. RESULTS Mean error between imputed and SILA‐estimated age at A+ ( N = 26) was 1.15 years. Age at A+ explained 39% of estimated years to symptom onset (EYO) variance. Time from A+ explained 19% of cognitive composite variance and 14% of Clinical Dementia Rating Sum of Boxes CDR‐SB variance; EYO explained 43% and 57%, respectively. DISCUSSION SILA estimates A+ age in ADAD with reasonably good accuracy. SILA‐estimated time from A+ describes the start of pathology, but the time from A+ onset to symptoms is variable in ADAD and better described by EYO. Highlights Amyloid chronicity predicts a 14‐year preclinical AD phase in ADAD. SILA accurately estimates age at A+ (MAE < 2 years). EYO outperforms chronicity in predicting symptom onset. APP mutation carriers show atypical amyloid accumulation. Chronicity models help reveal AD heterogeneity in preclinical stages.

Abstract BACKGROUND Tau‐derived cerebrospinal fluid (CSF) biomarkers correlate with amyloid‐beta (Aβ) plaques or tau tangles in Alzheimer's disease (AD). This study assessed the effects of long‐term anti‐Aβ antibodies on amyloid plaques, tau tangles, and CSF tau species to determine the relationships between them. METHODS A post‐hoc analysis of the DIAN‐TU‐001 trial (NCT01760005) examined 142 participants at risk for dominantly inherited AD randomized to solanezumab ( n = 50), gantenerumab ( n = 52), or placebo ( n = 40). High‐resolution mass spectrometry quantified CSF tau species over four years. RESULTS Phosphorylated tau (p‐tau) species (153, 181, 217, 231) increased early in preclinical AD but were reduced with gantenerumab‐mediated Aβ plaque reduction. Nearly a decade later, MTBR‐tau243 and p‐tau205 increased, showing no association with Aβ reduction, aligning with tau tangle pathology progression. DISCUSSION Initially changing soluble p‐tau species track Aβ plaque reduction, while ptau205 and MTBR‐243 reflect tau tangle pathology, informing different pathways of therapeutic strategies. Highlights p‐tau217 and p‐tau231 correlate with Aβ‐PET and respond to Aβ‐plaque lowering therapies. Aβ immunotherapy trials support a direct link between p‐tau changes and Aβ plaques Gantenerumab reduces Aβ plaques but does not affect tau NFT‐related biomarkers. Blood‐based p‐tau217 assays may provide a non‐invasive tool to monitor Aβ therapies. MTBR‐tau243 strongly correlates with tau PET and tracks NFT pathology progression. Further studies are needed to validate tau biomarkers for tracking NFT‐targeting therapies.