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Objectives: To evaluate evolving management, ICU admission, and outcomes for critically ill chimeric antigen receptor (CAR) T-cell patients over a 6-year period. Design: Multicenter retrospective cohort study from January 2018 to September 2023. Setting: Eight U.S. centers. Patients: Adult CAR T-cell patients requiring ICU admission. Interventions: None. Methods: Summary statistics included mean, sd , median, and interquartile range (IQR). Fisher exact test or chi-square test were used to evaluate association between year treated and other categorical variables. Cochran-Armitage test was performed to assess significance of trends across years. Multivariable logistic regression was performed to assess covariates associated with mortality. Measurements and Main Results: Demographics, toxicity management, ICU admission, support modalities, toxicity severity, and survival (ICU, hospital, and 3-mo) were compared year-to-year. From 2018 to 2023, 2238 patients received CAR T cells, with increasing number of patients treated yearly; 398 (17.8%) required ICU care. Of those admitted to the ICU, 66.1% were male, 89.2% had lymphoma, and median age was 64 years (53–71 yr). ICU admission rates declined from 38.5% (95% CI, 31.6–45.8%) in 2018 to 16.4% in 2023 (95% CI, 13.5–19.7%; p < 0.0001). Cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome was the reason for ICU admission in 87.9%. In 2023 vs. 2018, ICU patients were older (median, 65 yr [IQR, 55–73 yr] vs. 58 yr [48–67 yr]; p = 0.003) with higher comorbidity indices (4 [4–6] vs. 3 [2–4]; p = 0.005) and more severe toxicities (≥ grade 3: 90.1% vs. 69.9%; p = 0.004). Corticosteroid use for less severe toxicities (≤ grade 2 toxicity: 73.8% vs. 40.6%; p = 0.0001) and anakinra use (56% vs. 5.5%; p < 0.0001) increased throughout the years. Mortality from cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome remained low (5.5%). Age, Sequential Organ Failure Assessment greater than or equal to 10 at ICU admission, and ICU admission for noncytokine release/neurotoxicity syndrome reasons were associated with hospital mortality (odds ratios, 1.02 [95% CI, 1–1.04; p = 0.046], 4.69 [2.44–9.01; p < 0.0001], and 3.74 [1.91–7.3; p = 0.0001], respectively). Conclusions: ICU admission rates after CAR T-cell treatment are declining. Although ICU patients are older with higher severity of illness and toxicity grades, ICU mortality after CAR T-cell therapy remains low.

Abstract Cockayne Syndrome is an ultra-rare premature aging condition associated with UV sensitivity, neurocognitive decline, retinopathy, metronidazole-induced lethality, and sensorineural hearing loss. In 70% of affected patients, bi-allelic pathogenic variants in ERCC6 are identified. Although the role of ERCC6 in DNA damage repair has been studied, little is known about the mechanism for defective ERCC6 function in clinical findings, particularly hearing loss. To identify the mechanism of disease caused by pathogenic variants in ERCC6, we developed a zebrafish (Danio rerio) ercc6 loss of function model. We assessed survival after UV and metronidazole exposure, measured basal respiration rates, and evaluated mechanoelectrical transduction function and counts of lateral line hair cells. We found that UV exposure significantly reduces ercc6−/− larval viability. Metronidazole treatment results in complete lethality; wildtype controls show nearly complete survival. ercc6−/− embryos have significantly increased oxygen consumption, suggesting abnormal mitochondrial function. Phalloidin staining of lateral line hair cells with and without UV treatment shows no difference in hair cell counts per neuromast between treatment groups. Mechanoelectrical transduction function after UV exposure, measured by FM1–43 uptake, is reduced. Metronidazole lethality is reduced, oxygen consumption rates are restored, and mechanoelectrical transduction function is preserved by treatment with Mn(III)tetrakis(4-benzoic acid)porphyrin Chloride (MnTBAP), a superoxide dismutase mimetic. We propose that defective mitochondrial function and increased reactive oxygen species levels provide a mechanism for hair cell dysfunction in this model of Cockayne Syndrome. These results provide a foundation for further experiments to explore disease mechanisms and treatment modalities for this premature aging condition.

Abstract Purpose: Mutant IDH1 (mIDH1) defines a therapeutically targetable subtype of intrahepatic cholangiocarcinoma (ICC), with the mIDH1 inhibitor ivosidenib approved for advanced disease. A subset of patients experiences prolonged disease stabilization; however, the molecular basis for eventual progression remains poorly defined. Experimental Design: We performed molecular profiling of matched baseline and postprogression circulating tumor DNA (ctDNA) samples from patients with mIDH1 ICC enrolled in the ClarIDHy phase III trial. Functional studies were conducted to characterize candidate resistance mechanisms. Results: Longitudinal ctDNA analysis of 18 patients treated with ivosidenib for &gt;6 months revealed emergent genomic alterations in multiple cases. Acquired mutations in mitogen-activated protein kinase (MAPK) pathway genes (KRAS, NRAS, MAP2K1, NF1) were identified in five cases, with instances of concurrent alterations and/or high variant allele fractions (VAF). Additional candidate resistance events included a secondary IDH1 mutation and a hotspot IDH2 mutation, detected at low VAF in the same patient. Functional studies showed that these IDH mutations conferred sustained 2-hydroxyglutarate production and ivosidenib resistance, whereas MAPK activation blunted gene expression induced by ivosidenib plus IFNγ, a key therapeutic output of mIDH1 inhibition. In parallel, baseline ctDNA profiling of 81 patients revealed that ARID1A mutations and elevated mIDH1 VAF were associated with reduced clinical benefit. Conclusions: MAPK pathway alterations represent a recurrent mechanism of resistance to mIDH1 inhibition in ICC, whereas emergent IDH1/IDH2 mutations appear infrequent. Functional data suggest that MAPK-mediated resistance may involve impaired IFN signaling. These results support MAPK-directed combination strategies and highlight the utility of ctDNA profiling to identify predictive and resistance biomarkers in mIDH1-driven ICC.

Abstract Background and Aims Celiac disease (CeD) is a chronic digestive autoimmune disorder affecting approximately 1% of the worldwide population. It is driven by T cells activated by specific HLA-DQ2 or HLA-DQ8 molecules leading to the destruction of intestinal villi. We aimed to characterize shared CeD-specific T cells in patients on and off a gluten-free diet (GFD) from a large cohort of cases and controls. Methods We performed bulk TCRβ immune sequencing of the peripheral blood of 1,604 biopsy-confirmed CeD patients (1,339 on GFD, 265 on normal diet) and 1,100 controls. We identified over 300 TCRβs enriched in CeD cases versus controls in an HLA-aware manner, controlling for CeD risk alleles. Results CeD-associated TCRβs were found to be more predictive of disease than previously characterized gliadin and glutenin-binding TCRs in a validation cohort. Furthermore, the clonal breadth of these TCRβs was associated with increased intestinal damage. Immune sequencing of the peripheral blood also uncovered repertoire-level differences between CeD patients and controls. CeD patients displayed significantly higher productive clonality compared to age-matched controls as well as expansion of TCRβs specific to cytomegalovirus (CMV) and Epstein-Barr Virus (EBV). Conclusions These findings underscore the value of unbiased immune repertoire sequencing to identify novel biomarkers for autoimmune disease and to discover new disease mechanisms which can improve both diagnosis and treatment of disease.

Abstract Background TMEM106B encodes a lysosomal protein and is a genetic susceptibility factor for frontotemporal lobar degeneration (FTLD). Aptamer‐based proteomics quantifies TMEM106B protein levels in CSF. The associations of CSF TMEM106B with measures of disease severity have not been previously evaluated, and the value of CSF TMEM106B as a clinical biomarker is unknown. Method CSF TMEM106B and NfL protein levels were quantified with aptamer‐based proteomics in participants from two independent cohorts: sporadic FTLD with neuropathology‐confirmed FTLD‐tau and FTLD‐TDP, clinically diagnosed PSP‐Richardson Syndrome, and controls (UCSF MAC, n = 95; mean age = 69 ± 6 yrs; 48% female) and familial FTLD comprised of presymptomatic and symptomatic FTLD mutation carriers with family non‐carrier controls (ALLFTD, n = 179; mean age = 49 ± 13 yrs; 53% female). The association between biomarkers and diverse measures of disease severity, including the CDR®+NACC‐FTLD and CDR®+NACC‐FTLD sum of boxes, were determined with linear regressions or mixed linear models. Associations with brain volumes were determined within the framework of voxel‐based morphometry. Result In both cohorts, at baseline, CSF TMEM106B did not differ by sex, age, FTLD phenotype, or CSF NfL. CSF TMEM106B was lower in cases with worse disease severity (Figure 1) and in participants with the protective TMEM106B rs1990622 G/G genotype, regardless of pathological diagnosis or FTLD‐causing mutation. Low CSF TMEM106B was associated with more severe longitudinal worsening in FTLD disease severity (Figure 2), basic and instrumental function, global cognition, executive function, and depression scores. These associations were weaker than those of NfL. Low CSF TMEM106B was associated with low brain volumes in frontal, parietal, and temporal regions (FWE‐corrected p < 0.05) (Figure 3A). CSF NfL negatively correlated (FWE‐corrected p < 0.05) with brain volumes in frontotemporal regions (Figure 3B). Conclusion CSF TMEM106B concentrations are influenced by the TMEM106B rs1990622 genotype, and correlate with disease severity and brain volume in both genetic and sporadic FTLD. Lower levels of CSF TMEM106B correlate with more severe disease and brain atrophy. Disease severity is more strongly associated with CSF NfL, while brain volumes are more strongly associated with CSF TMEM106B. CSF TMEM106B may have value as a biomarker of neurodegeneration in FTLD.

Abstract Background The Alzheimer's Association workgroup criteria (AA‐2024) suggest four biological stages based on PET imaging. However, the application of this framework may vary depending on the tau PET tracer used, and the distribution of clinical stages by biological stage may differ. Here, we aim to compare the diagnostic performance of the biological staging of Alzheimer Disease using two different tau PET tracers. Method We analyzed 446 individuals and further stratified 167 Aβ‐positive participants from the HEAD study (Longitudinal multicenter head‐to‐head harmonization of tau PET tracers) that underwent both MK‐6240 and Flortaucipir (FTP) tau PET. Four clinical stages (normal, transitional, MCI, and dementia) were defined based on the AA‐2024 criteria. Within stage‐2 we assessed subgroups: subjective cognitive decline (SCD), subtle objective cognitive decline (SOCD), and mild behavioral impairment (MBI). Logistic and linear models corrected by age and sex tested association of groups with amyloid and tau pathology. The biological staging was performed using tracer‐specific thresholds for regional SUVR and testing two regions of interest schemes: (i) proposed by AA‐2024 and (ii) Braak stages (Figure 1). Cohen's weighted‐kappa (K) statistic measured clinical‐biological agreement. Positive predictive value (PPV) of an individual being clinically impaired (MCI or dementia) was calculated for each biological stage. Result Clinical stages showed a progressively increased prevalence of Aβ‐positivity and higher entorhinal tau PET pathology from cognitively normal (CN) to SOCD, MCI, and dementia in both tracers. MBI and SCD transitional groups showed no increased Aβ or tau pathology compared to CN (Figure 2). For this reason, only SOCD was considered part of stage 2 for following analyses. All tested biological staging strategies showed moderate agreement (0.34‐0.59) with clinical stages using either tracers. The distribution of biological across clinical stages were similar for FTP and MK, with MK‐6240 showing lower PPV values in earlier stages than FTP (Table 1). Conclusion Our results support that AA‐2024 biological and clinical stages show similar clinical‐biological concordance using either Flortaucipir or MK‐6240, although this can vary based on methods tested in the study. The MBI and SCD clinical subgroups showed no difference of pathological burden to clinical stage 1, while SOCD transitional stage showed higher burden compared to stage 1.

Abstract Background HEAD is a longitudinal, multi‐site, non‐randomized study aiming to harmonize different tau PET tracers onto a common scale for enrichment and monitoring of anti‐tau clinical trials. To achieve this, the Uniτ scale is being developed using data from participants scanned head‐to‐head with Flortaucipir and MK6240, with a subset also scanned with PI2620 and RO948. However, access to the Uniτ scale has been limited to the study community and collaborators. To address this limitation, we have developed the Uniτ Ecosystem – a set of tools for tau PET harmonization designed to support research and clinical trials ( www.unitau.app ). Method The Uniτ Ecosystem was developed for multiple operating systems (Web/macOS/Windows/Ubuntu) (Figure 1) and currently include four tools. The Uniτ harmonization is an online ROI harmonization module that allows the user to harmonize SUVRs from spreadsheets. The Uniτ packages (R, Python and MATLAB) facilitates the transformation of SUVR values to the Uniτ scale using the most used programming languages in research settings. The Uniτ calculator app allows rapid and convenient harmonization. The Uniτ desktop app is a 3D harmonization module for voxel‐wise harmonization. The Uniτ parameters were calculated using a training set of 200 participants with head‐to‐head MK6240 and Flortaucipir, and 90 individuals with additional PI2620 and RO948. Researchers can use their own datasets and convert tau PET data to the Uniτ scale. Result The online ROI harmonization module allows users to harmonize tau PET SUVRs uploaded from spreadsheets and offers interactive visualizations such as scatter plots and histograms for tau positivity thresholds (Figure 2). The calculator app enables users to harmonize single SUVR values effortlessly. The desktop application for 3D tau PET harmonization leverages the functionalities of the previous modules to harmonize entire 3D images, eliminating the need for predefined ROIs. Additionally, this module provides visualization tools for the parametric Uniτ images in 2D and 3D (Figure 3). Uniτ tools never store any data on any external servers. Conclusion The Uniτ Ecosystem represents a significant advance in tau PET harmonization, providing a user‐friendly platform to harmonize and visualize tau PET data for research and clinical trials.

Abstract Background Tau PET tracers present distinct binding characteristics that might influence their trajectories and relationship with other biomarkers along the AD continuum. In a head‐to‐head study, we investigated the relationship between the emergence of PET tracers MK6240 and Flortaucipir, and plasma p ‐tau217 abnormalities as a function of Aβ PET deposition. We further assessed the concordance between tau PET and plasma p ‐tau217 positivity and its relationship with cognitive scores. Method We evaluated 352 individuals from the HEAD study (205 cognitively unimpaired and 147 cognitively impaired) with Aβ PET, MK6240 and Flortaucipir tau PET, and plasma p ‐tau217 (ALZpath) and GFAP (Quanterix) measures. Tau PET Braak regions, plasma p ‐tau217 trajectories were modeled as functions of Aβ burden (Centiloid scale) using the Lowess method. Biomarkers were z‐scored anchored on young individuals ( n = 19, < 28 years old) as anchors. Tau PET (Braak 1 region) and plasma p ‐tau217 were considered positive/abnormal when surpassing 2.5 z‐score. Result Among the tested markers, MK6240 was the earliest to show abnormality as a function of Centiloid, occurring at 22 Centiloids, followed by plasma p ‐tau217 at 38 Centiloid and Flortaucipir at Centiloid 56 (Figure 1). Tau PET and plasma p ‐tau217 positivity showed an overall high concordance (∼80% for both tracers; Figure 2). In MK6240 discordant cases, most individuals were MK6240+/p‐tau217‐ (13.8%), while 6.6% were MK6240‐/p‐tau217+ (Figure 2A). For Flortaucipir, 15% of discordant cases were Flortaucipir‐/p‐tau217+, while 4.8% were Flortaucipir+/p‐tau217‐ (Figure 2B). The discordant groups present higher Centiloid than the ptau217‐/Tau‐ group and overall decreased scores in cognitive tests, except for p ‐tau217+/MK6240‐ group (Figure 3). Conclusion MK6240 becomes abnormal at lower levels of Aβ burden compared to plasma p ‐tau217 and Flortaucipir. The relatively high prevalence of discordant tau PET positive or plasma p ‐tau217 positive and suggests that some individuals may show tau PET positivity first, while others may exhibit plasma p ‐tau217 positivity first. The distinct cognitive profiles of this groups suggest potential clinical relevance, warranting further investigation.

Abstract Background Individuals with preclinical AD are difficult to detect using traditional clinical tools. Yet, many individuals classified as cognitively unimpaired (CU) can exhibit a heterogeneous pattern of subtle clinical abnormalities, potentially linked to early Alzheimer's disease (AD). Primary care providers often have access only to clinical tests to study at‐risk community‐dwelling older adults who visit them without cognitive complaints. Since early intervention is crucial in AD, identifying clinical tools to detect preclinical AD is important in areas with limited access to blood or imaging biomarkers. In this study, we evaluate the link between Montreal Cognitive Assessment (MoCA) total scores and AD pathology in CU individuals. Methods We studied 204 cognitively unimpaired (CU) older adults who underwent both 18 F‐FTP and 18 F‐MK6240 scans. These individuals were stratified based on their amyloid PET status, determined by visual reading, into CU A+ ( n = 35) and CU A‐ ( n = 137), as part of the ongoing HEAD study. CU adults had Clinical Dementia Rating (CDR) of 0 and were clinically identified as non‐MCI and non‐demented. Voxel‐wise linear regression models tested the association between MoCA total scores and tau pathology. Results CU A+T+ had significantly lower total MoCA scores than A‐T‐ individuals (Figure 1). Lesser MoCA total score was significantly associated with greater mediobasal temporal tau deposition, using both 18 F‐MK6240 and 18 F‐FTP [Figure 2]. When we separated the population by Aβ status, we found that these results were driven by the CU A+ group (Figure 3A) and were not present in CU A‐ individuals (Figure 3B). Discussion These findings indicate that the MoCA, a simple routine in‐office clinical test, can detect subtle cognitive dysfunction associated with preclinical AD. This suggests that simple cognitive testing can play a role in the early detection of AD and therefore an option for prescreening older adults in non‐specialized clinical settings, the initial interface for most older adults without cognitive complaints. Conclusion MoCA total, the common dementia screening test also plays a valuable role in detecting preclinical AD.

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.