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Background: The renin-angiotensin-aldosterone system (RAAS) has been associated with gastrointestinal inflammation and fibrosis, suggesting that RAAS blockade may be beneficial in patients with inflammatory bowel disease. Using retrospective analysis, we aimed to compare the disease course of patients with Crohn’s disease (CD) taking two commonly prescribed classes of RAAS-blocking agents. Study: Patients with CD initiated on an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) between 2000 and 2016 were enrolled. Data on clinical, radiologic, and procedural surrogate markers of inflammatory bowel disease were collected in the subsequent 3, 5, and 10 years and compared with matched controls using univariate and multivariate analyses. Results: Compared with controls, patients taking ARBs had fewer instances of corticosteroid use (1.06 vs 2.88, P < 0.01) at 10 years. Patients taking ACEIs had an overall worse disease course, with more imaging studies (3.00 vs 1.75, P = 0.03) and endoscopic procedures (2.70 vs 1.78, P = 0.01) at 5 years, and more imaging studies (6.19 vs 3.50, P < 0.01), endoscopic procedures (5.91 vs 3.78, P < 0.01), and gastrointestinal operations (0.59 vs 0.18, P < 0.02) at 10 years. Results remained significant on multivariate analysis, adjusting for CD characteristics and the use of other antihypertensive medications. Conclusions: Our study provides insight into the long-term use of RAAS-blocking agents in patients with CD, suggesting that differences exist among commonly prescribed medication classes. While ACEIs were associated with an overall worse disease course at 5 and 10 years, patients taking ARBs were noted to have fewer instances of corticosteroid use at 10 years. Future large-scale studies are needed to further explore this association.

We previously demonstrated that increased expression of the SERPINA5 gene is associated with hippocampal vulnerability in Alzheimer’s disease (AD) brains. SERPINA5 was further demonstrated to be a novel tau-binding partner that colocalizes within neurofibrillary tangles. Our goal was to determine whether genetic variants in the SERPINA5 gene contributed to clinicopathologic phenotypes in AD. To screen for SERPINA5 variants, we sequenced 103 autopsy-confirmed young-onset AD cases with a positive family history of cognitive decline. To further assess the frequency of a rare missense variant, SERPINA5 p.E228Q, we screened an additional 1114 neuropathologically diagnosed AD cases. To provide neuropathologic context in AD, we immunohistochemically evaluated SERPINA5 and tau in a SERPINA5 p.E228Q variant carrier and a matched noncarrier. In the initial SERPINA5 screen, we observed 1 individual with a rare missense variant (rs140138746) that resulted in an amino acid change (p.E228Q). In our AD validation cohort, we identified an additional 5 carriers of this variant, resulting in an allelic frequency of 0.0021. There was no significant difference between SERPINA5 p.E228Q carriers and noncarriers in terms of demographic or clinicopathologic characteristics. Although not significant, on average SERPINA5 p.E228Q carriers were 5 years younger at age of disease onset than noncarriers (median: 66 [60–73] vs 71 [63–77] years, P = .351). In addition, SERPINA5 p.E228Q carriers exhibited a longer disease duration than noncarriers that approached significance (median: 12 [10–15]) vs 9 [6–12] years, P = .079). More severe neuronal loss was observed in the locus coeruleus, hippocampus, and amygdala of the SERPINA5 p.E228Q carrier compared to noncarrier, although no significant difference in SERPINA5-immunopositive lesions was observed. Throughout the AD brain in either carrier or noncarrier, areas with early pretangle pathology or burnt-out ghost tangle accumulation did not reveal SERPINA5-immunopositive neurons. Mature tangles and newly formed ghost tangles appeared to correspond well with SERPINA5-immunopositive tangle-bearing neurons. SERPINA5 gene expression was previously associated with disease phenotype; however, our findings suggest that SERPINA5 genetic variants may not be a contributing factor to clinicopathologic differences in AD. SERPINA5-immunopositive neurons appear to undergo a pathologic process that corresponded with specific levels of tangle maturity.

AbstractBackgroundGene expression changes have been identified in post‐mortem brain tissue of AD cases when compared with controls, implicating various genes and pathways. Such findings provide important insights into molecular dysregulation associated with this disease and nominate therapeutic targets. Here we investigate brain gene and co‐expression network changes in a cohort of AD cases to identify associations with degree of AD neuropathology including Braak stage (Tau), Thal phase (Amyloid beta) and brain tissue levels of five AD‐related proteins (apoE, Aβ40, Aβ42, tau, and p‐tau).MethodGene expression measures were collected from temporal cortex (TCX) tissue of 477 AD cases, available through the Mayo Clinic Brain Bank, using RNA sequencing (Illumina TruSeq mRNA) performed on the HiSeq4000. Following quality control 456 cases remained for analysis. Braak and Thal were provided by an experienced neuropathologist and TCX levels of five AD‐related proteins from three fractions (buffer‐soluble, detergent‐soluble, and insoluble) were measured by ELISA (Liu et al. 2020). Weighted gene coexpression network analysis (WGCNA) R package was used to build co‐expression networks. Genes and networks were tested for association with neuropathology and AD‐related protein levels, adjusting for relevant covariates.ResultA total of 57,353 genes were profiled, of which 19,044 were reliably expressed above background levels and formed 20 co‐expression modules. 36 genes were associated with Braak stage, 10 with Thal phase and up to 9,000 with the AD‐related protein fractions. Brain levels of pTau had the greatest number of associations, with an overrepresentation of genes involved in synaptic signalling and immune response gene ontology biological processes. 16 of the coexpression modules associated with at least one trait after Bonferroni correction for number of tests.ConclusionWe have identified a number of genes and networks associated with different aspects of AD neuropathology and associated proteins, further lending support to the involvement of synaptic and immune biology in AD. However it is not clear whether observed changes cause disease or are a consequence of the neurodegenerative process. Comparison of these findings across different proteins and fractions is expected to reveal common and distinct vulnerabilities associated with amyloid and tau, and different stages of protein aggregation.

AbstractIntroductionWe examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early‐onset Alzheimer's disease (EOAD; onset 40‐64 years) at the midway point of data collection for the Longitudinal Early‐onset Alzheimer's Disease Study (LEADS).MethodsBaseline NPS (Neuropsychiatric Inventory – Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups – amyloid‐positive EOAD (n = 212) and amyloid negative early‐onset non‐Alzheimer's disease (EOnonAD; n = 70).ResultsAffective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD.DiscussionOverall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late‐onset AD.

7515 Background: Outcomes are poor for patients (pts) with cHL who develop R/R disease after first-line (1L) chemotherapy ± radiotherapy (RT). Salvage tx that attain high event-free survival (EFS) rates and minimize late toxicity by omitting high-dose chemotherapy (HDCT)/auto-HCT are needed. CheckMate 744 (NCT02927769) is the first multicenter phase 2 study evaluating a risk-stratified, response-adapted salvage tx with nivo + BV in CAYA with R/R cHL. In the standard-risk cohort, complete molecular response (CMR) rate before consolidation with HDCT/auto-HCT was 94% (Harker-Murray et al. Blood 2022). With highly active salvage tx, pts in low-risk cohort could achieve high EFS without HDCT/auto-HCT; we report data from this cohort. Methods: Pts were aged 5–30 y and had ≤ 3 cycles (C) of 1L anthracycline-based systemic tx. Risk stratification was described in Harker-Murray et al. Pts received 4C of nivo + BV induction. Pts with CMR received additional 2C nivo + BV before involved-site radiation therapy (ISRT) consolidation (dose, 30–30.6 Gy). Pts with suboptimal response received 2C BV + bendamustine intensification; pts with CMR proceeded to ISRT consolidation. Primary endpoints: CMR rate (Lugano 2014) any time before ISRT and 3-y EFS rate, both per blinded independent central review (BICR). For CMR and overall response rate (ORR), a 90% confidence interval (CI) was used per statistical plan. Results: Among 28 pts treated with nivo + BV, median (range) age was 17 (6–27) y; 64% of pts were aged < 18 y. Most (64%) pts had stage II disease at relapse; 82% had relapse ≥ 12 mo after 1L tx, 2 pts had prior RT. Median (range) follow-up was 31.9 (2.2–55.3) mo. CMR, ORR, 3-y EFS and PFS rates are shown in Table. Median duration of response was not reached; 87% of pts had sustained response at 36 mo’ follow-up. Efficacy outcomes were comparable in the pediatric population (CMR per BICR before ISRT, 88.9%; 3-y EFS rate, 78.3%). During induction, 22 (78.6%) pts had treatment-related adverse events (TRAEs; grade 3/4, 25.0% pts; hematologic, < 10% pts; immune-mediated, 21.4%). Serious AEs leading to discontinuation included rash, pyrexia, and acute kidney injury (1 pt each). Conclusions: The findings demonstrate that most CAYA with low-risk R/R cHL can be salvaged with chemoimmunotherapy with a favorable toxicity profile, and do not require HDCT/auto-HCT. Clinical trial information: NCT02927769 . [Table: see text]

e14531 Background: Afami-cel is an autologous, T-cell receptor T-cell therapy engineered to target melanoma-associated antigen A4 (MAGE-A4) in human leukocyte antigen (HLA) A*02–eligible patients (pts) with advanced solid tumors. SPEARHEAD-1 (NCT04044768) is a Phase 2, two cohort, open-label trial to evaluate the efficacy and safety of afami-cel in pretreated pts with advanced/metastatic synovial sarcoma or myxoid/round cell liposarcoma. Here we report data on cytokine release syndrome (CRS) in the pts with advanced synovial sarcoma treated with afami-cel across Cohort 1 and Cohort 2. Methods: Eligible pts had advanced synovial sarcoma and were HLA-A*02 positive with MAGE-A4–positive tumors. Pts received afami-cel after lymphodepleting chemotherapy containing fludarabine and cyclophosphamide. Tocilizumab administration was permitted for Grade 1 CRS if symptoms persisted for ≥ 24 hours or if the pt had co-morbidities, and for Grade ≥2 CRS. Results: As of August 29, 2022, 72 pts with synovial sarcoma received afami-cel (n = 44 Cohort 1; n = 28 Cohort 2). Afami-cel dose range was 1.92–10.00×109 transduced T-cells. The median age was 39.5 years (range: 16–73 years), 47.2% of pts were female, 88.3% of pts were white, and tumor MAGE-A4 expression H-score was 244.5 (range: 66–300). CRS occurred in 72.2% of the pts with synovial sarcoma receiving afami-cel, including Grade 1 in 50% (36/72), Grade 2 in 20.8% (15/72), and Grade 3 in 1.4% (1/72) of pts as per American Society for Transplantation and Cellular Therapy grading. The median time to onset was 2.5 days (range: 1–5 days), and the median time to resolution was 3 days (range: 1 to 14 days). Twenty-seven of 72 (37.5%) pts received at least one dose of tocilizumab. Consistent with expectations, higher serum IL-6 levels were associated with CRS events and the indicated use of tocilizumab for management. RECIST v1.1 responses were observed in pts with and without CRS. Correlation of clinical factors and CRS with response will be presented. Conclusions: CRS was common after afami-cel administration but was mostly low grade. Administration of tocilizumab in SPEARHEAD-1 was effective in the management of CRS. Clinical trial information: NCT04044768 .

Abstract Alpha‐synuclein (αsyn) aggregates are pathological features of several neurodegenerative conditions including Parkinson disease (PD), dementia with Lewy bodies, and multiple system atrophy (MSA). Accumulating evidence suggests that mitochondrial dysfunction and impairments of the autophagic‐lysosomal system can contribute to the deposition of αsyn, which in turn may interfere with health and function of these organelles in a potentially vicious cycle. Here we investigated a potential convergence of αsyn with the PINK1‐PRKN‐mediated mitochondrial autophagy pathway in cell models, αsyn transgenic mice, and human autopsy brain. PINK1 and PRKN identify and selectively label damaged mitochondria with phosphorylated ubiquitin (pS65‐Ub) to mark them for degradation (mitophagy). We found that disease‐causing multiplications of αsyn resulted in accumulation of the ubiquitin ligase PRKN in cells. This effect could be normalized by starvation‐induced autophagy activation and by CRISPR/Cas9‐mediated αsyn knockout. Upon acute mitochondrial damage, the increased levels of PRKN protein contributed to an enhanced pS65‐Ub response. We further confirmed increased pS65‐Ub‐immunopositive signals in mouse brain with αsyn overexpression and in postmortem human disease brain. Of note, increased pS65‐Ub was associated with neuronal Lewy body‐type αsyn pathology, but not glial cytoplasmic inclusions of αsyn as seen in MSA. While our results add another layer of complexity to the crosstalk between αsyn and the PINK1‐PRKN pathway, distinct mechanisms may underlie in cells and brain tissue despite similar outcomes. Notwithstanding, our finding suggests that pS65‐Ub may be useful as a biomarker to discriminate different synucleinopathies and may serve as a potential therapeutic target for Lewy body disease.

AbstractObjectiveThe Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early‐onset Alzheimer's disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data‐collection mid‐point.MethodsData from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [n = 89], amyloid‐positive EOAD [n = 212], and amyloid‐negative early‐onset non‐Alzheimer's disease [EOnonAD; n = 70]).ResultsCognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (APOE) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures.ConclusionsWe present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in APOE ε4 allele carrier status appearing to be relevant.HIGHLIGHTS Findings represent the most comprehensive baseline characterization of sporadic early‐onset Alzheimer's disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups. EOAD participants were homozygous apolipoprotein E (APOE) ε4 carriers at higher rates than the EOnonAD group. Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present.