Glucose hypometabolism is observed in early Alzheimer's disease. However, there are regional discrepancies in hypometabolism and Alzheimer's pathological markers. We examined the local and global contributions of amyloid-β and tau pathology to glucose metabolism and their interplay in memory decline in Presenilin-1 E280A mutation carriers and non-carriers from the largest autosomal-dominant Alzheimer's disease kindred. This cross-sectional study included 43 mutation carriers (6 cognitively impaired) and 39 non-carriers from the Colombia-Boston Biomarker Study. Glucose metabolism was assessed with [18F]fluorodeoxyglucose PET, and memory performance with the Consortium to Establish a Registry for Alzheimer's Disease word list learning. A subgroup of 22 carriers and 26 non-carriers additionally had measures of amyloid-β and tau using 11C-Pittsburgh compound B and 18F-flortaucipir PET, respectively. First, we compared regional glucose metabolism between groups using the Wilcoxon rank-sum test. Then, we studied regional glucose metabolism associations with age, co-localized amyloid-β and tau pathology, and memory using Spearman correlation. Local specificity was assessed by partial correlations controlling for global amyloid-β and tau burden. Finally, we studied whether the link between Alzheimer's pathology and memory was mediated by regional glucose hypometabolism. Mutation carriers exhibited lower glucose metabolism in the precuneus and isthmus cingulate compared to non-carriers. Hypometabolism correlated locally with greater tau accumulation in the medial temporal lobe, inferior temporal gyrus and prefrontal cortex, and with greater amyloid-β accumulation in the inferior temporal gyrus in carriers. These associations were no longer significant when controlled for global pathology, except for the frontal tau-hypometabolism correlation, which was independent of global tau burden, suggesting local specificity. Additionally, lower memory performance in carriers was associated with hypometabolism in regions typically affected by tau. The mediation analysis revealed a region-specific interplay in pathology, with the associations of amyloid-β and tau pathology with memory decline being mediated by hypometabolism in the inferior temporal. Our findings highlight the metabolic vulnerability of the precuneus in early stages, supporting a common pathophysiology between autosomal-dominant and sporadic Alzheimer's disease. The lack of local correlations between amyloid-β, tau and hypometabolism suggests that distant effects may explain the regional discrepancies between pathology accumulation and metabolic alterations. This study describes a model where pathology advances and interacts in a region-specific manner to impact clinical outcomes, underscoring the importance of regional [18F]fluorodeoxyglucose PET as an independent predictor of cognitive decline. Overall, our findings improve understanding of the spatial progression of pathology, which could have important implications in disease management.
Publications by Year: 2026
2026
BACKGROUND: Living near greenspace is associated with decreased cardiovascular disease (CVD). Greenspace estimates, however, typically represent all types of vegetation using top-down satellite images, which incorporate exposure misclassification and limit policy relevance.
OBJECTIVE: We studied the association between street-view greenspace measures with incident CVD using a large, long-term prospective US cohort of female nurses.
METHODS: We estimated the percentage of streetscapes composed of visible trees, grass, and other green (plants/flowers/fields) from 350 million street-view images using deep learning models. Estimates were applied to Nurses' Health Study participants (N = 88,788) within 500 m of their residential addresses. We used Cox models to estimate associations from 2000 to 2018 between street-view greenspace measures and risk of incident CVD, assessed through self-report, medical record review, or death certificates, and adjusted for individual- and area-level factors.
RESULTS: In adjusted models, higher percentages of visible trees were associated with lower CVD incidence (hazard ratio [HR] per interquartile range [IQR] 0.96 (95% confidence interval 0.93, 1.00]), while higher percentages of visible grass (HR 1.06 [1.02, 1.11]) and other green space types (HR 1.03 [1.01, 1.04]) were associated with higher CVD incidence. We did not observe evidence of effect modification by population density, Census region, air pollution, satellite-based vegetation, or neighborhood socioeconomic status. Findings were robust to adjustment for other spatial and behavioral factors and persisted even after adjustment for traditional satellite-based vegetation indices.
DISCUSSION: Specific greenspace types may be protective or harmful for CVD. Aggregating greenspace into a single exposure category limits epidemiological research and potential interventions to increase health-promoting greenspace.
INTRODUCTION: Endogenous measures of impaired kidney tubule secretion are associated with kidney function decline. Whether they associate with future acute kidney injury (AKI) risk is unclear.
METHODS: In 397 participants of the Reasons for Geographic and Racial Differences in Stroke study who underwent coronary artery bypass graft (CABG) surgery (mean age: 66 years, 29% female), we examined the association of a summary secretion score of 11 endogenous secretion markers (measured at a median 5.5 years before CABG) with AKI risk following CABG, adjusting for confounders including estimated glomerular filtration rate (eGFR) and albuminuria.
RESULTS: A total of 177 participants developed AKI (≥ 0.3 mg/dl or 1.5× creatinine increase) following CABG. Individuals who developed AKI were older, more likely to be men, have diabetes, lower eGFR and greater albuminuria at the baseline visit. In models adjusted for age, sex, race, urine creatinine, time from baseline to CABG, diabetes, hypertension, and body mass index, a higher (signifying better) secretion score was associated with lower risk of AKI (risk ratio [RR] comparing 4th to 1st quartile: 0.49, 95% confidence interval [CI]: 0.32-0.74). The results did not meaningfully differ after further adjusting for eGFR and albuminuria (RR: 0.58, 95% CI: 0.38-0.89), or when secretion score was analyzed as a continuous variable (RR per 1 SD higher score: 0.85, 95% CI: 0.71-1.01). Associations were stronger in women (RR: 0.75, 95% CI: 0.59-0.95) than men (RR: 0.89, 95% CI: 0.69-1.16) in fully adjusted models (P interaction = 0.01).
CONCLUSION: In community-based adults, greater estimated tubular secretion at times of relative health is associated with lower risk of AKI following CABG.
BACKGROUND: Effective cardiovascular disease (CVD) risk management is essential for optimal diabetes care. Here, we estimated the prevalence and determinants of CVD risk factor control among individuals with diagnosed diabetes in Mexico.
METHODS: We analyzed data from individuals ≥20 years with diagnosed diabetes from 2016 to 2023 Mexican National Health and Nutrition Surveys. We estimated the prevalence of glycemic, blood pressure, noncurrent smoking, low-density lipoprotein cholesterol, and combined CVD risk factor control. We estimated use of blood pressure-lowering, cholesterol-lowering, and glucose-lowering medication and explored determinants of control achievement using logistic regression.
RESULTS: We analyzed data from 2916 participants, representing 43.2 million adults with diagnosed diabetes during 2016 to 2023. In 2023, glycemic control was 29% (95% CI, 21%-38%), blood pressure control 22.9% (95% CI, 14%-31%), and noncurrent smoking 89% (95% CI, 81%-96%). The prevalence of high or very-high CVD risk using Systematic Coronary Risk Evaluation 2-Diabetes increased from 59.8% (95% CI, 52.1%-67.0%) in 2016 to 68.4% (95% CI, 55.6%-78.9%) in 2023, representing 5.1 million adults. Low-density lipoprotein cholesterol control increased from 2.8% (95% CI, 1.2%-4.4%) in 2016 to 6.6% (95% CI, 1.9%-11.2%) in 2023 and statin use from 5.5% in 2016 to 63% in 2023. Combined risk factor control achievement was low due to suboptimal low-density lipoprotein cholesterol control and was more likely achieved in women, younger individuals, and those with college education or living in states with higher socioeconomic position.
CONCLUSIONS: Despite increasing CVD risk during this period, glycemic and CVD risk factor management for adults with diabetes in Mexico remains suboptimal. Our findings suggest a need for strategies to improve CVD risk management to reduce diabetes-related mortality and complications.
The authors of this commentary published two peer-reviewed online articles in 2020 and 2022 on the U.S. Agency for Healthcare Research and Quality (AHRQ) PSNet that were removed by the Trump administration because they violated White House policy on websites that "inculcate or promote gender ideology." Ours were among thousands of articles and websites that had been removed or censored during the first month of the Trump administration. We describe the details of this censorship of our two articles one on suicide prevention, the other on endometriosis diagnosis challenges, neither of which was directly related to LGBT issues but used what are now banned terms. We further discuss the historical and political context of this removal, and the subsequent merger of AHRQ into a new Trump administration "Office of Strategy" that purports to target "the effectiveness of federal health programs" for improvement. In light of these censorship actions, large scale staff layoffs, and this reorganization, the fate of AHRQ's mission, current activities, and future project funding is currently uncertain. We offer strategic suggestions for resisting such attacks on academic freedom and restoring scientific integrity for patient safety, quality, and public health.
UNLABELLED: There is significant interest in antigen-specific approaches to delaying type 1 diabetes in preclinical stages and supporting tolerance after diagnosis. We conducted a phase I trial of a nonintegrating DNA plasmid constructed to secrete the type 1 diabetes antigen preproinsulin (PPI) and the immune modulatory cytokines transforming growth factor-β1 (TGF-β1), interleukin-10 (IL-10), and IL-2. In this placebo-controlled, double-masked study of 47 adults with stage 3 type 1 diabetes, we showed that the drug is safe and well tolerated, with most reported adverse events (AEs) categorized as grade 1 and with no clinically significant difference in AEs among treatment groups. There were no untoward metabolic or immune effects. We found pharmacodynamic evidence of treatment, as demonstrated by a dose-dependent type 1 interferon (IFN) signature. Plasmid DNA, representing a pharmocokinetic measure, was detected in the two highest dosing groups. We did not find global or antigen-specific immune cell changes following treatment with a DNA plasmid expressing PPI, IL-2, IL-10, and TGF-β1, and we did not detect immune changes driven by IL-2, IL-10, or TGF-β1. Our results support further trials of this novel tolerizing antigen construct.
ARTICLE HIGHLIGHTS: Antigen-specific therapy is needed to induce tolerance in type 1 diabetes at early disease stages or in combination with immunotherapy. We conducted a phase I trial in type 1 diabetes of a novel plasmid construct expressing the islet antigen preproinsulin (PPI) and immunomodulatory cytokines transforming growth factor-β1 (TGF-β1), interleukin-10 (IL-10), and IL-2. The therapy was safe and well tolerated. Dose-dependent changes in DNA plasmid levels and type 1 interferon signatures were detected; however, global and antigen-specific immune changes to PPI, IL-2, IL-10, or TGF-β1 were not observed. Further trials are needed to assess efficacy.
BACKGROUND: The 148M variant of PNPLA3 is a major genetic risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), yet its macrophage-specific role remains unclear. We investigated how PNPLA3-148M alters macrophage behavior and multicellular liver pathology under lipotoxic stress.
METHODS: We used a human induced pluripotent stem cell (iPSC)-derived multicellular liver culture comprising hepatocytes, hepatic stellate cells (HSCs), and isogenic macrophages that differed only at PNPLA3 (148M vs. 148I). Cultures were exposed to lipotoxic conditions to induce MASLD. We quantified inflammatory cytokines, oxidative stress, hepatocyte lipid accumulation, and HSC activation. Macrophage death pathways were profiled (apoptosis, pyroptosis, necroptosis), with emphasis on RIPK3 expression and phosphorylation. Downstream effects on hepatocytes and HSCs were assessed.
RESULTS: Under lipotoxic stress, 148M macrophages amplified MASLD-like features. PNPLA3 transcripts were induced in macrophages-rising in iPSC-derived macrophages from lipotoxic cultures, and in Kupffer cells isolated from murine MASLD. Single-cell RNA-seq further confirmed PNPLA3 expression in human liver macrophage clusters, in addition to hepatocytes and HSCs. Although PNPLA3 mRNA was comparable between genotypes, 148M macrophages displayed higher PNPLA3 protein and increased necroptosis, evidenced by elevated RIPK3 expression and phosphorylation without changes in apoptosis or pyroptosis. Integrative analyses identified NACC1 as a key transcriptional regulator of RIPK3, with NF-κB-linked upregulation of NACC1 in 148M macrophages. NACC1 inhibition (genetic or NIC3) reduced RIPK3, suppressed necroptosis, and lowered pro-inflammatory cytokine secretion. NIC3 additionally decreased hepatocyte lipid accumulation and ATP and diminished HSC activation markers.
CONCLUSIONS: The PNPLA3 148M variant promotes MASLD through a macrophage-specific NF-κB-NACC1-RIPK3 axis that enhances necroptosis and inflammatory signaling, thereby exacerbating hepatocyte steatosis and HSC activation. NACC1 emerges as a tractable therapeutic target for genetically at-risk individuals.
BACKGROUND: Measurement of cardiac troponin (cTn) using high-sensitivity assays is recommended for the diagnosis of myocardial infarction. We determined sex-specific and uniform 99th percentile upper reference limits (URLs) using the new Elecsys® Troponin T high-sensitivity Gen 6 assay in a global, healthy reference range cohort.
METHODS: Lithium-heparin (Li-Hep) plasma and serum samples were prospectively collected from apparently healthy individuals aged ≥20 years across 34 global sites in the United States, Europe, China, and Japan. cTnT was measured using the Troponin T high-sensitivity Gen 6 assay on the Cobas® e 801 analyzer. Exclusion criteria were defined according to the 2022 International Federation of Clinical Chemistry guidance. Uniform and sex-specific 99th percentile URLs and non-parametric 95% confidence intervals (CI) were determined in plasma and serum separately and combined.
RESULTS: The final study population comprised 4147 participants (52.5% female) with a median (25-75th percentiles) age of 48.0 (33.0-59.0) years; 45.8%, 47.9%, 5.2% and 1.1% were White, Asian, Black, and other/unknown, respectively. For sample matrices combined (n=8294), 81.0% and 99.2% of cTnT values were above the limit of detection in females and males, respectively. Sex-specific 99th percentile URLs (95% CI) were 18 (16-23) ng/L for females and 32 (28-35) ng/L for males; the uniform 99th percentile URL was 27 (24-31) ng/L. URLs were comparable in plasma and serum samples.
CONCLUSIONS: This study determined sex-specific and uniform 99th percentile URLs for the Troponin T high-sensitivity Gen 6 assay that were comparable irrespective of the matrix used, in a large, global, healthy reference population.