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ABSTRACT Aims Metabolic dysfunction‐associated steatotic liver disease (MASLD) is increasingly linked to cognitive decline, yet the hepatic factors associated with imaging‐derived neurovascular coupling (NVC) remain unclear. This study aimed to investigate whether liver stiffness or liver fat content was more closely associated with resting‐state CBF‐ReHo surrogate measures. Materials and Methods A total of 130 participants including 98 MASLD patients and 32 age‐ and education‐matched healthy controls (HCs) underwent clinical assessment, neuropsychological testing, and multi‐modal MRI. Liver stiffness and fat content were quantified using MR elastography (MRE) and MRI‐proton density fat fraction (PDFF). Imaging‐derived NVC was assessed using global cerebral blood flow (CBF)‐regional homogeneity (ReHo) coupling and voxel‐wise CBF/ReHo ratios, interpreted as resting‐state surrogates rather than direct stimulus‐evoked NVC. Multivariable regression and exploratory mediation analyses were employed. Results Compared to HCs and patients with lower liver stiffness (MASLD_low), those with higher liver stiffness (MASLD_high) showed reduced global CBF‐ReHo coupling and altered CBF/ReHo ratios, primarily localized to the bilateral superior temporal pole/superior temporal gyrus (TPOsup). In multivariable regression, liver stiffness remained independently associated with TPOsup CBF/ReHo ratios ( p < 0.001). Exploratory mediation analysis showed a statistically significant indirect association between hepatocellular injury markers and TPOsup CBF/ReHo ratios involving MRE‐derived liver stiffness (95% CI: 0.0795–0.2790). Conclusions Within this cohort and the observed PDFF range, MRE‐derived liver stiffness was more closely associated with imaging‐derived NVC surrogate measures than liver fat content in MASLD. These findings are hypothesis‐generating and require validation in longitudinal studies.

Abstract Background The treatment (tx) landscape for chronic lymphocytic leukemia (CLL) has evolved, with National Comprehensive Cancer Network (NCCN) guideline-preferred novel therapies (NTs), such as acalabrutinib, zanubrutinib, and venetoclax-based regimens, now preferred over ibrutinib and chemoimmunotherapy (CIT) in front-line (1L) settings. We previously showed that patients (pts) from different racial/ethnic groups may not have equitable access to NTs. Here, we examined racial/ethnic inequities in 1L NT utilization among US pts with CLL and potential social determinants of health (SDOH) drivers of these inequities. Methods This retrospective cohort study utilized the US-based, electronic health record-derived de-identified Flatiron Health Research Database, linked to neighborhood (US Census track or block group) data from American Community Survey and Agency for Healthcare Research and Quality datasets. Eligible pts included adults with CLL who started 1L tx 01/01/2019-07/31/2024. The primary outcome was receipt of 1L therapy (CIT vs preferred NTs, ibrutinib vs preferred NTs), with NCCN guideline-preferred NTs (v2.2023-v3.2025) as a reference. Associations between race/ethnicity (White, Black, Hispanic) and 1L tx types were assessed using logistic regressions, adjusting for age, sex, year of 1L start, immunoglobulin heavy chain variable region status, and del17p/TP53 status. To better understand which SDOH factors contribute to racial and ethnic inequities in tx utilization, we performed mediation analysis using Multiple Mediation Analysis implemented through nonlinear multiple additive regression tree models. Individual-level (Eastern Cooperative Oncology Group status, practice type, insurance) and 20 area-level SDOH factors measuring social deprivation (defined as limited access to economic, social, neighborhood, physical, or healthcare resources) were assessed as potential mediators. Results Of the 4452 pts included in the study, 3717 were White (83%), 371 were Black (8%), 209 were Hispanic (5%), and 155 were Other race (4%). Black and Hispanic pts were more likely to live in neighborhoods with higher social deprivation, such as residential segregation (predominant race/ethnicity in the area: White, Black, Hispanic, Diverse), with no internet access, no vehicle ownership, and no health insurance coverage. Overall, 37% of pts received a preferred NT, highest among White (38%) pts, followed by Black (35%) and Hispanic (26%) pts. Compared with White pts, Hispanic pts were more likely to receive CIT than preferred NTs (adjusted odds ratio [aOR] 2.12; 95% confidence interval [CI] 1.46-3.09); Black (aOR 1.44; 95% CI 1.05-1.97) and Hispanic pts (aOR 1.83; 95% CI 1.17-2.85) were more likely to receive ibrutinib than preferred NTs. Pts living in areas with the highest social deprivation were less likely than their counterparts in lowest social deprivation neighborhoods to receive preferred NTs. Specifically, residence in predominantly Black or Hispanic neighborhoods (26% or 27% vs 39% predominantly White), areas with lowest socioeconomic status (32% vs 40%), and neighborhoods with the lowest levels of internet access (32% vs 39%), vehicle ownership (32% vs 39%), and health insurance coverage (34% vs 41%) was associated with lowest receipt of preferred NTs. In the mediation analysis, individual- and area-level SDOH factors explained 94.4% (95% CI 2.9-185.9) of the observed Black-White inequity in receipt of ibrutinib versus preferred NTs; residential segregation appeared to be the most important mediator (59.7%; 95% CI −3.5 to 123.0). Similarly, the Hispanic-White inequity in receipt of preferred NTs was driven by the combined effect of area-level SDOH and individual-level variables (88.5%; 95% CI 45.6-131.3), with residential segregation as the main driver (48.3%; 95% CI 10.7-85.9), followed by practice setting (9.8%; 95% CI −3.5 to 23.1). In contrast, measured SDOH factors did not explain the inequity in receipt of CIT versus preferred NTs between Hispanic and White pts (21.5%; 95% CI −8.3 to 51.4), suggesting that other factors may contribute to the observed inequities. Conclusion Black and Hispanic pts with CLL were less likely than White pts to receive preferred NTs. A significant proportion of these disparities was explained by area-level SDOH, particularly residential segregation. These findings underscore the need to address structural barriers to ensure equitable access to emerging, guideline-recommended treatments.

Abstract Aims Activating transcription factor 4 (ATF4) functions as a transcriptional regulator in various cell types and tissues under both physiological and pathological conditions. While previous studies have linked ATF4 activation with promoting cardiomyocyte (CM) death in dilated cardiomyopathy (DCM), atrial fibrillation, and heart failure, its role in developing CMs remains unexplored. Methods and results We generated multiple distinct CM-specific (Atf4cKO(e2/3/pA) and Atf4cKO(e2)) and global Atf4 knockout (KO; Atf47del/7del and Atf41ins/1ins) mouse models targeting different Atf4 regions, as well as CM-specific deletion of Rps19bp1 to study cardiac phenotypes. Detailed morphological and molecular analyses were performed. Atf4cKO(e2/3/pA) [targeting exon 2–3 including the polyadenylation signal (polyA)] mice exhibited severe cardiac defects and died before E17.5, likely due to ectopic activation of the p53 signaling pathway resulting from Rps19bp1 downregulation, a potent suppressor of p53. Further investigation revealed that deleting the polyA signal of Atf4 in Atf4cKO(e2/3/pA) mice led to transcriptional readthrough, resulting in the formation of an Atf4-Cacna1i fusion transcript and Rps19bp1 downregulation. To avoid readthrough while abolishing ATF4 function, we introduced small indels into exon 3 of Atf4 in mice (Atf47del/7del and Atf41ins/1ins), which showed normal Rps19bp1 expression and cardiac morphology. Importantly, CM-specific deletion of Rps19bp1 recapitulated the cardiac defects and transcriptional change seen in Atf4cKO(e2/3/pA) mice. Conclusion We found that the downregulation of Rps19bp1, not the loss of ATF4 function, underlies the cardiac phenotypes in Atf4cKO(e2/3/pA) mice. The reduced expression of Rps19bp1 in Atf4cKO(e2/3/pA) mice is likely due to the unintentional deletion of Atf4 polyA signal and subsequent transcriptional readthrough, underscoring the essential role of RPS19BP1, not ATF4, in cardiac development. Consistent Rps19bp1 downregulation has been observed in other tissue-specific Atf4 KO models utilizing the Atf4fl(e2/3/pA) allele, suggesting that previously reported Atf4 KO phenotypes may result from Atf4 transcriptional readthrough effects. These findings reveal a locus-dependent transcriptional interference mechanism and emphasize the importance of avoiding confounding cis effects in genetically engineered models.

Background Studies suggest that plasma Alzheimer's disease (AD) biomarkers may aid in the overall diagnosis of AD, but their utility among patients with atypical clinical presentations of AD are unknown. Objective The main objective of this study was to determine the relationship between amyloid-β (Aβ) and tau plasma biomarkers and PET measures of both Aβ and tau in atypical AD. The secondary objective was to determine if plasma biomarkers could differentiate patients with different atypical AD phenotypes and whether they were related to measures of disease severity. Methods We assessed whether plasma p-tau 181 and Aβ 42/40 were associated with Aβ and tau PET uptake, clinical phenotype and severity in 77 patients with PET biomarker-confirmed atypical AD. Results Plasma Aβ 42/40 ratio showed positive associations with tau PET uptake, with higher (more normal) Aβ 42/40 ratio associated with higher tau uptake; the ratio was not associated with Aβ PET. No associations were noted with plasma p-tau 181. Plasma Aβ 42/40 ratio and p-tau 181 concentrations were not associated with AD phenotype or cognitive severity. Conclusion Plasma Aβ 42/40 ratio and p-tau 181 concentrations are not associated with amyloid or tau PET or with clinical severity among individuals presenting with atypical AD.

AbstractBackgroundBlood plasma metrics provide excellent biomarkers of the presence of Alzheimer’s disease (AD) pathology in population cohorts. However, it is less clear whether plasma metrics correlate with PET measures of AD pathology in cohorts of patients with advanced AD disease, particularly in those with atypical clinical presentations of AD.MethodSeventy‐seven patients (visual variant=43, language variant=32, motor variant=1 and dysexecutive variant=1) with PET biomarker‐confirmed atypical AD were recruited by the Neurodegenerative Research group at Mayo Clinic, Rochester, MN, underwent Aβ (Pittsburgh Compound‐B) and tau (18F‐flortaucipir) PET and provided a blood sample. Blood plasma analysis was performed to assess p‐tau 181 and Aβ42/40 ratio concentrations using the Quanterix Simoa platform. Multivariate linear regression models assessed the relationship between plasma concentrations and both global Aβ, atypical AD summary and regional tau PET measures. For each PET measure, two separate models were fit to assess the influence of each plasma biomarker separately, while the third model included all plasma measures to assess the combined influence of all biomarkers on PET uptake. To investigate differences in plasma concentrations between atypical AD phenotypes, we performed Mann‐Whitney’s test across the visual and language variants of AD.ResultPlasma Aβ42/40 ratio showed positive associations with tau PET uptake, specifically within precuneus, parietal and temporal regions and was not associated with Aβ PET. There was no relationship between plasma p‐tau 181 and Aβ or tau PET uptake. However, the model that included both plasma biomarkers showed that with the addition of p‐tau 181, all significant associations between Aβ42/40 ratio and regional tau uptake were weakened to trends. The Aβ42/40 ratio continued to show no relationship with global Aβ‐PET uptake and plasma p‐tau 181 showed no relationship to PET measures (Figure 1). Lastly, no significant difference in plasma Aβ42/40 and p‐tau 181 levels was noted between the visual and language variants of AD (Figure 2).ConclusionThe lack of associations between plasma concentrations and PET measures of Aβ and tau in this relatively advanced AD cohort may suggest that plasma concentrations have greater utility as diagnostic biomarkers of early AD as compared to advanced AD.

AbstractINTRODUCTIONGlial fibrillary acidic protein (GFAP) in plasma is a proxy for astrocytic activity and is elevated in amyloid‐β (Aβ)‐positive individuals, making GFAP a potential blood‐based biomarker for Alzheimer's disease (AD).METHODSWe assessed plasma GFAP in 72 Aβ‐positive participants diagnosed with the visual or language variant of AD who underwent Aβ‐ and tau‐PET. Fifty‐nine participants had follow‐up imaging. Linear regression was applied on GFAP and imaging quantities.RESULTSGFAP did not correlate with Aβ‐ or tau‐PET cross‐sectionally. There was a limited positive correlation between GFAP and rates of tau accumulation, particularly in the language variant of AD, although associations were weaker after removing one outlier patient with the highest GFAP level.DISCUSSIONAmong Aβ‐positive AD participants with atypical presentations, plasma GFAP did not correlate with levels of AD pathology on PET, suggesting that the associations between GFAP and AD pathology might plateau during the advanced phase of the disease.

AbstractBackgroundPhysical activity is associated with reduced risk for Alzheimer’s disease (AD). Aerobic exercise produced modest‐to‐moderate cognitive gains in older adults with mild cognitive impairment or AD dementia. In animal models, aerobic exercise modifies AD’s AT(N) biomarkers of Amyloid‐beta (Aβ), hyperphosphorylated Tau, and Neurodegeneration. However, most observational studies didn’t find significant associations between physical activity and AT(N) biomarkers. Few exercise trials included biomarkers, partially attributable to the prohibitive cost and invasiveness of cerebrospinal fluid or PET biomarkers and reported mixed effects on central AT(N) biomarkers. Plasma Aβ42/40 ratio, phosphorylated tau 181 (p‐tau181), and total tau (t‐tau) demonstrate robust correlations with central amyloid and tau levels and offer an opportunity for inclusion in exercise trials.MethodThis pilot study examined the preliminary effects of 6‐month aerobic exercise on plasma Aβ42/40 ratio, p‐tau181, and t‐tau in older adults with mild‐to‐moderate AD dementia. Twenty‐six participants were eligible, and all consented to enroll (8 in stretching, 18 in cycling). Plasma Aβ42/40 ratio, p‐tau181, and t‐tau were measured using Simoa™ assays at baseline, 3, and 6 months. Data were analyzed using Cohen’s d, multilevel model, and intention‐to‐treat.ResultThe sample averaged 77.58±6.99 years old, 15.44±3.00 years of education, 65% male, and 96.2% carrying an APOE e4 allele. The 6‐month within‐group trajectories of changes in outcomes trended differently but were not statistically significant. Aβ42/40 ratio (mean ± standard deviation) increased by 0.001±0.012, p‐tau181 increased by 0.609±1.417 pg/ml, and t‐tau decreased by 0.020±0.279 ng/ml in the stretching group, while Aβ42/40 ratio decreased by 0.001±0.010, p‐tau181 increased by 0.101±1.579 pg/ml, and t‐tau decreased by 0.075±0.215 pg/ml in the cycling group. Between‐group differences were not significant. Effect sizes for 6‐month within‐group changes were small except for p‐tau181 in stretching (d = 0.43 [‐.65, 1.45]) and t‐tau in cycling (‐0.35 [‐0.87, 0.17]). Most 6‐month between‐group effect sizes were also small except for p‐tau181 (d = .40 [‐.70, 1.51]) and t‐tau (d = .53 [‐.40, 1.46]), a trend favoring cycling.ConclusionBlood biomarkers are highly feasible and tolerable. Exercise modalities may affect AD plasma biomarkers differently. Aerobic exercise may reduce p‐tau181 levels and stretching exercise may improve Aβ42/40 ratio, which need to be validated in future trials.

Neurodevelopmental disorders are associated with metabolic pathway imbalances; however, most metabolic measurements are made peripherally, leaving central metabolic disturbances under-investigated. Cerebrospinal fluid obtained intraoperatively from children with autism spectrum disorder (ASD, n = 34), developmental delays (DD, n = 20), and those without known DD/ASD (n = 34) was analyzed using large-scale targeted mass spectrometry. Eighteen also had epilepsy (EPI). Metabolites significantly related to ASD, DD and EPI were identified by linear models and entered into metabolite–metabolite network pathway analysis. Common disrupted pathways were analyzed for each group of interest. Central metabolites most involved in metabolic pathways were L-cysteine, adenine, and dodecanoic acid for ASD; nicotinamide adenine dinucleotide phosphate, L-aspartic acid, and glycine for EPI; and adenosine triphosphate, L-glutamine, ornithine, L-arginine, L-lysine, citrulline, and L-homoserine for DD. Amino acid and energy metabolism pathways were most disrupted in all disorders, but the source of the disruption was different for each disorder. Disruption in vitamin and one-carbon metabolism was associated with DD and EPI, lipid pathway disruption was associated with EPI and redox metabolism disruption was related to ASD. Two microbiome metabolites were also detected in the CSF: shikimic and cis-cis-muconic acid. Overall, this study provides increased insight into unique metabolic disruptions in distinct but overlapping neurodevelopmental disorders.