Articles publicats (Medicina Experimental)
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- ItemOpen AccessOrexin, Sleep, and Cognition in Alzheimer Disease: Non-REM Oscillatory Activity and Neural Resilience(Wolters Kluwer Health, 2026) Paez, Arsenio; Piñol Ripoll, Gerard; Carnes-Vendrell, Anna; Dakterzada, Farida; Barbé Illa, Ferran; Zetterberg, Henrik; Dang-Vu, Thien ThanhBackground and objectives: Sleep-wake dysregulation and elevated CSF orexin have been implicated in Alzheimer disease (AD). Sleep spindles (SPs) and slow oscillations (SOs) are linked to cognition and neurodegeneration; however, their relationship with CSF orexin concentrations in symptomatic AD has not been characterized. We investigated whether nonrapid eye movement (NREM) SP-SO activity is associated with CSF orexin and whether these oscillatory features moderate associations between orexin, cognition, neuropsychiatric symptom severity, and AD biomarkers. Methods: This prospective observational cohort study was conducted at a tertiary memory clinic in Lleida, Spain. Individuals aged ≥60 years with biomarker-confirmed mild-to-moderate AD (National Institute on Aging-Alzheimer's Association criteria) underwent overnight polysomnography and morning CSF sampling. SP and SO were detected using validated automated algorithms with independent verification and visual quality control. CSF was assayed for orexin-A, amyloid-β42 (Aβ42), phosphorylated tau181 (pTau181), total tau, and YKL-40. Cognitive performance Alzheimer's Disease Assessment Scale-Cognitive Subscale ([ADAS-Cog], Mini-Mental State Examination (MMSE), California verbal learning test, ROCF) and neuropsychiatric symptoms (NPI) were assessed longitudinally over 36 months. Associations were examined using generalized linear models with robust estimators adjusted for age, sex, Aβ42, and apnea-hypopnea index. Multiple comparisons were controlled using false discovery rate correction. Interaction terms assessed moderation effects. Results: Sixty participants (30 women; mean age 74.7 years) were included. Longer SO duration and higher SP density and power were associated with lower CSF orexin concentrations (SP density: β = -187.37 pg/mL, 95% CI -344.93 to -29.80). Orexin was not associated with global sleep continuity metrics. Higher CSF orexin concentrations were associated with worse global cognition (ADAS-Cog: β = 0.014, 95% CI 0.003-0.024; MMSE: β = -0.01, 95% CI -0.011 to -0.004) and greater neuropsychiatric symptom severity (NPI at: β = 0.03, 95% CI 0.011-0.041). Higher orexin was also associated with higher pTau181 (β = 0.11, 95% CI 0.04-0.19), total tau, and YKL-40 (β = 0.37, 95% CI 0.17-0.57). Significant orexin × SP-SO interactions were observed, such that greater oscillatory activity attenuated the adverse associations between orexin and cognitive outcomes, independent of Aβ42 and tau. Discussion: In biomarker-confirmed AD, NREM SP and SO activity are associated with CSF orexin concentrations and moderate associations between orexin and longitudinal cognitive and neuropsychiatric outcomes. Limitations include the observational design and absence of a comparator group, precluding causal inference and limiting contextualization relative to normal aging. NREM oscillatory metrics and orexin concentrations may represent complementary physiologic markers for disease monitoring and therapeutic targeting. Trial registration information: Role of Hypoxia and Sleep Fragmentation in AD; ClinicalTrials.gov Identifier: NCT02814045.
- ItemOpen AccessEffects of aged black garlic (ABG10+) on lipoprotein subclass composition in Grade I hypertension: a randomized, triple-blind controlled trial with sex-stratified sequential allocation(Frontiers Media, 2026) Serrano Casasola, José Carlos Enrique; Castro-Boqué, Eva; García-Carrasco, Alicia; Morán-Valero, María Inés; Díez Municio, Marina; Bermúdez López, Marcelino; Valdivielso, José Manuel; Espinel, Alberto E; Portero Otín, ManuelBackground: Aged black garlic (ABG) is rich in organosulfur compounds such as S-allyl-cysteine (SAC) and may influence lipid metabolism, although evidence from controlled trials remains limited. The aim of this study was to evaluate the impact of a low-dose SAC-optimized ABG on blood lipid profiles in Grade I hypertensive individuals. Methods: A randomized, triple-blind, placebo-controlled trial with systematic sex-stratified sequential allocation was conducted with 75 Grade I hypertensive participants receiving either 250 mg of ABG or a placebo daily for 12 weeks. Plasma lipoproteins and subclass composition were quantified by NMR spectroscopy, and metabolic clusters were explored using k-means and PLS-DA. Results: ABG supplementation did not produce statistically significant changes in any conventional lipid marker (total cholesterol, LDL-C, HDL-C, or triglycerides). In secondary exploratory analyses of NMR-derived lipoprotein subclasses, nominally significant differences were observed: ABG was associated with a reduction in the total number of particles and HDL particles. Detailed analysis of XXL-VLDL particles showed a decrease in the percentage of free and esterified cholesterol alongside an increase in triglyceride percentage. Large HDL particles showed compositional remodeling characterized by an increase in phospholipid content and a decrease in triglyceride percentage. In exploratory cluster analyses, participants with a more adverse baseline metabolic profile showed a nominally significant reduction in total triglycerides and VLDL-lipid content after ABG intake. Conclusion: Low-dose ABG supplementation did not significantly modify conventional lipid markers in Grade I hypertensive individuals. However, secondary exploratory NMR-based analyses suggest that ABG may induce compositional remodeling of lipoprotein subclasses-particularly reducing the cholesterol load in large VLDL particles and enhancing HDL phospholipid content-especially in individuals with a more adverse baseline metabolic profile. These findings are hypothesis-generating and require confirmation in adequately powered trials with pre-specified NMR endpoints. Clinical trial registration: identifier: NCT04915053.
- ItemOpen AccessLong-term safety and immunogenicity of ABvac40 active immunotherapy in mild cognitive impairment and very mild Alzheimer's disease: Results from AB1601 phase 2 extension study(Wiley, 2026) Pascual-Lucas, María; Lacosta, Ana María; Montañés, María; Canudas, Jesús; Loscos, Jorge; Monleón, Inmaculada; Allué, José Antonio; Sarasa, Leticia; Fandos, Noelia; Romero, Judith; Sarasa, Manuel; Torres, Mireia; Whyms, Dermot; Terencio, Jose; Piñol Ripoll, Gerard; Boada, MercèIntroduction: ABvac40 is an active immunotherapy targeting Aβ40, the main component of cerebrovascular deposition in Alzheimer's disease (AD). A 24-month randomized, placebo-controlled phase 2 study (Part A) showed favorable safety and robust immunogenicity, with exploratory signals of clinical efficacy. Here, we report results from Part B, an 18-month extension evaluating long-term safety and immunological memory. Methods: Participants treated with ABvac40 in Part A received placebo plus a delayed booster, whereas previous placebo participants received ABvac40. Exploratory endpoints included safety, tolerability, and immunogenicity. Results: Seventy-seven participants entered Part B. Treatment-emergent adverse events (TEAEs) occurred in 75.0% of participants in placebo + booster group and 81.1% in ABvac40 group; serious TEAEs were 5.0% and 16.2%, respectively. No ARIA-E or meningoencephalomyelitis were observed, with one ARIA-H event. ABvac40 induced robust antibody responses following delayed booster, with detectable anti-Aβ40 antibodies in CSF. Discussion: ABvac40 showed favorable long-term safety and durable immunogenicity, supporting further clinical development. Trial registration: ClinicalTrials.gov: NCT03461276, registered March 2, 2018. EudraCT: 2016-004352-30, registered March 10, 2017.
- ItemOpen AccessAssociation of Triglyceride-Glucose Index With Femoral but Not Carotid Atherosclerosis in Chronic Kidney Disease: A Two-Sample Mendelian Randomization Study(Elsevier, 2026) Cambray Carner, Serafí; Marti-Antonio, Manuel; Bermúdez López, Marcelino; Garcia-Carrasco, Alicia; Pérez Sánchez, Carlos Javier; Martín Conde, María Luisa; Valdivielso, Jose M.Objective: Patients with chronic kidney disease (CKD) have a higher risk of cardiovascular events than matched non-CKD individuals. The triglyceride-glucose (TyG) index is a calculated metric used to predict cardiometabolic risk. Although TyG is associated with cardiovascular events in CKD, its relationship with atherosclerotic burden remains unexplored. This study aimed to investigate this association using Mendelian randomization (MR) METHODS: Subjects from the NEFRONA study with ultrasound assessment of atherosclerotic plaque presence in 6 carotid and 4 femoral arterial territories were included. Multivariable linear regression models were used to explore the association between TyG index and atherosclerotic burden. Two-sample MR was employed to assess whether the TyG index has a causal effect on the number of carotid and femoral plaques. Results: 358 controls, 709 CKD G3, 569 CKD G4-5 and 463 dialysis subjects were included. Higher TyG levels, analyzed as a continuous variable or by quartiles, were positively associated with the number of plaques in both territories. After multivariable adjustment, the association with femoral plaques remained statistically significant both as a linear variable (beta = 0.11; P = .02) and by quartiles (Q3 vs Q1: beta = 0.16; P = .026; Q4 vs Q1: beta = 0.17; P = .026; Tendency analysis: beta = 0.06; P = .02). Several unadjusted MR methods showed an effect of genetic variants associated with higher TyG levels on femoral, but not carotid, atherosclerosis. Multivariable inverse-variance weighted analysis adjusted for multiple variables suggested a causal relationship between higher TyG index and the number of femoral plaques (estimate:0.95; 95% confidence interval: 0.1-1.80, P = .029). Conclusions: Our two-sample MR study suggests a causal effect of higher TyG index on subclinical atherosclerotic burden in femoral arteries in CKD. Genetic testing could be used to stratify the risk of lower-limb atherosclerosis in CKD patients.
- ItemEmbargoThe expanding role of Cav3 channels in glioblastoma(Elsevier, 2026) Casals, Maria; Herreros Danés, Judit; Cantí Nicolás, CarlesTumor-intrinsic voltage-gated Cav3 calcium channels, comprising the Cav3.1, Cav3.2 and Cav3.3 isoforms, have been implicated in cancer cell proliferation and survival. Recent work by Dube et al. reveals a role for microenvironmental Cav3.2 channels in glioblastoma, promoting neuron–cancer cell crosstalk and identifying changes in immune-related programs associated with Cav3.2 deficiency.