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Fil:Perissinotti, Luis José. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina

Quantitative informant- and self-reports of subjective cognitive decline predict amyloid beta PET outcomes in cognitively unimpaired individuals independently of age and APOE ε4

Introduction: Amyloid beta (Aβ) pathology is an Alzheimer's disease early hallmark. Here we assess the value of longitudinal self- and informant reports of cognitive decline to predict Aβ positron emission tomography (PET) outcome in cognitively unimpaired middle-aged individuals. Methods: A total of 261 participants from the ALFA+ study underwent [18F]flutemetamol PET and Subjective Cognitive Decline Questionnaire (SCD-Q) concurrently, and 3 years before scan. We used logistic regressions to evaluate the ability of SCD-Q scores (self and informant) to predict Aβ PET visual read, and repeated analysis of variance to assess whether changes in SCD-Q scores relate to Aβ status. Results: Self-perception of decline in memory (odds ratio [OR] = 1.2), and informant perception of executive decline (OR = 1.6), increased the probability of a positive scan. Informant reports 3 years before scanning predicted Aβ PET outcome. Longitudinal increase of self-reported executive decline was predictive of Aβ in women (P = .003). Discussion: Subjective reports of cognitive decline are useful to predict Aβ and may improve recruitment strategies

Brain alterations in the early Alzheimer's continuum with amyloid-β, tau, glial and neurodegeneration CSF markers

Higher grey matter volumes/cortical thickness and fluorodeoxyglucose uptake have been consistently found in cognitively unimpaired individuals with abnormal Alzheimer's disease biomarkers compared with those with normal biomarkers. It has been hypothesized that such transient increases may be associated with neuroinflammatory mechanisms triggered in response to early Alzheimer's pathology. Here, we evaluated, in the earliest stages of the Alzheimer's continuum, associations between grey matter volume and fluorodeoxyglucose uptake with CSF biomarkers of several pathophysiological mechanisms known to be altered in preclinical Alzheimer's disease stages. We included 319 cognitively unimpaired participants from the ALFA+ cohort with available structural MRI, fluorodeoxyglucose PET and CSF biomarkers of amyloid-β and tau pathology (phosphorylated tau and total tau), synaptic dysfunction (neurogranin), neuronal and axonal injury (neurofilament light), glial activation (soluble triggering receptor on myeloid cells 2, YKL40, GFAP, interleukin-6 and S100b) and α-synuclein using the Roche NeuroToolKit. We first used the amyloid-β/tau framework to investigate differences in the neuroimaging biomarkers between preclinical Alzheimer's disease stages. Then, we looked for associations between the neuroimaging markers and all the CSF markers. Given the non-negative nature of the concentrations of CSF biomarkers and their high collinearity, we clustered them using non-negative matrix factorization approach (components) and sought associations with the imaging markers. By groups, higher grey matter volumes were found in the amyloid-β-positive tau-negative participants with respect to the reference amyloid-β-negative tau-negative group. Both amyloid-β and tau-positive participants showed higher fluorodeoxyglucose uptake than tau-negative individuals. Using the obtained components, we observed that tau pathology accompanied by YKL-40 (astrocytic marker) was associated with higher grey matter volumes and fluorodeoxyglucose uptake in extensive brain areas. Higher grey matter volumes in key Alzheimer-related regions were also found in association with two other components characterized by a higher expression of amyloid-β in combination with different glial markers: one with higher GFAP and S100b levels (astrocytic markers) and the other one with interleukin-6 (pro-inflammatory). Notably, these components' expression had different behaviours across amyloid-β/tau stages. Taken together, our results show that CSF amyloid-β and phosphorylated tau, in combination with different aspects of glial response, have distinctive associations with higher grey matter volumes and increased glucose metabolism in key Alzheimer-related regions. These mechanisms combine to produce transient higher grey matter volumes and fluorodeoxyglucose uptake at the earliest stages of the Alzheimer's continuum, which may revert later on the course of the disease when neurodegeneration drives structural and metabolic cerebral changes

Reactive astrogliosis is associated with higher cerebral glucose consumption in the early Alzheimer's continuum

PURPOSE: Glial activation is one of the earliest mechanisms to be altered in Alzheimer's disease (AD). Glial fibrillary acidic protein (GFAP) relates to reactive astrogliosis and can be measured in both cerebrospinal fluid (CSF) and blood. Plasma GFAP has been suggested to become altered earlier in AD than its CSF counterpart. Although astrocytes consume approximately half of the glucose-derived energy in the brain, the relationship between reactive astrogliosis and cerebral glucose metabolism is poorly understood. Here, we aimed to investigate the association between fluorodeoxyglucose ([18F]FDG) uptake and reactive astrogliosis, by means of GFAP quantified in both plasma and CSF for the same participants. METHODS: We included 314 cognitively unimpaired participants from the ALFA + cohort, 112 of whom were amyloid-β (Aβ) positive. Associations between GFAP markers and [18F]FDG uptake were studied. We also investigated whether these associations were modified by Aβ and tau status (AT stages). RESULTS: Plasma GFAP was positively associated with glucose consumption in the whole brain, while CSF GFAP associations with [18F]FDG uptake were only observed in specific smaller areas like temporal pole and superior temporal lobe. These associations persisted when accounting for biomarkers of Aβ pathology but became negative in Aβ-positive and tau-positive participants (A + T +) in similar areas of AD-related hypometabolism. CONCLUSIONS: Higher astrocytic reactivity, probably in response to early AD pathological changes, is related to higher glucose consumption. With the onset of tau pathology, the observed uncoupling between astrocytic biomarkers and glucose consumption might be indicative of a failure to sustain the higher energetic demands required by reactive astrocytes

Determination of differential quantum yields in solution by electron paramagnetic resonance spectroscopy

Quantitative kinetic studies on the photochemistry of paramagnetic species in solution may be carried out by electron paramagnetic resonance (EPR) spectroscopy. A cylindrical cell can be used as photochemical reactor, but the internal diameter should be less than 1.7 mm in order to achieve the resonance of an aqueous sample in an X-band (9-10 GHz) spectrometer. In this paper we present a detailed analysis of the fractions of incident light that are reflected, transmitted and absorbed by a liquid solution in a quartz cylindrical cell placed in the optical cavity of an X-band EPR spectrometer. Since the photolysis cell is irradiated perpendicularly to its axis, variable angles of incidence have been considered to calculate the transmission and reflection coefficients from Fresnel equations. Polarization of light has been also taken into account in the evaluation of the coefficients. The procedure proposed here is adequate for the evaluation of the absorbed light in the determination of quantum yields. The continuous photolysis at 366 nm of symmetric chlorine dioxide (OClO) in aqueous solution was considered as an example. The initial differential quantum yield obtained for OCIO photodecomposition in aqueous solution was Φ366 = 0.55±0.04.Fil: Quiroga, Sandra Lujan. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; ArgentinaFil: Churio, Maria Sandra. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; ArgentinaFil: Perissinotti, Luis José. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; Argentin

Reaction of β-carotene with nitrite anion in a homogeneous acid system. An electron paramagnetic resonance and ultraviolet-visible study

Ultraviolet and visible spectroscopy was applied to characterize and to measure the concentration of β-carotene dissolved in a dioxane and water mixture. The reaction of β-carotene in the presence of nitrite anion and acid medium was studied at different temperatures. The reaction systems were homogeneous and were kept anaerobic. Pseudo-first-order rate constants in respect of β-carotene were measured in the range from 293 to 313 K and pH 5.8 ± 0.2. The energy of activation was calculated to be E a = 67.2 ± 3.4 kJ/mol. We interpolate a value that may have biological interest, k β-carotene(310 K) = (9.70±0.78) · 10−3 s−1, in the presence of 9.3 · 10−3 M nitrite anion. Electron paramagnetic resonance spectroscopy was applied to characterize and quantify a persistent intermediate radical generated in the reaction system described. The recorded spectra showed triplet-type signals with a peak-to-peak value of 12.7 G. Nearly the same triplet radical-type intermediates were detected when studying the following reaction systems in pure dioxane: nitrogen dioxide (NO2)/β-carotene, nitric oxide (NO)/β-carotene and NO/NO2/β-carotene. Therefore, we proposed that the nitrogen oxides have also been intermediates in the reaction system of β-carotene, nitrite anion and acid medium, in the dioxane and water mixture. A mechanism was proposed and checked by employing the chemical kinetics simulation. The explanations developed would lead to a better understanding of the behavior of carotenoids in the presence of nitrite anion and nitrogen oxides.Fil: Mendiara, Sara Noemí. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; ArgentinaFil: Baquero, Romina Paola. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; ArgentinaFil: Katunar, Maria Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; ArgentinaFil: Mansilla, Andrea Yamila. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; ArgentinaFil: Perissinotti, Luis José. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentin

Quantitative informant‐ and self‐reports of subjective cognitive decline predict amyloid beta PET outcomes in cognitively unimpaired individuals independently of age and APOE ε4

Introduction: Amyloid beta (Aβ) pathology is an Alzheimer's disease early hallmark. Here we assess the value of longitudinal self- and informant reports of cognitive decline to predict Aβ positron emission tomography (PET) outcome in cognitively unimpaired middle-aged individuals. Methods: A total of 261 participants from the ALFA+ study underwent [18F]flutemetamol PET and Subjective Cognitive Decline Questionnaire (SCD-Q) concurrently, and 3 years before scan. We used logistic regressions to evaluate the ability of SCD-Q scores (self and informant) to predict Aβ PET visual read, and repeated analysis of variance to assess whether changes in SCD-Q scores relate to Aβ status. Results: Self-perception of decline in memory (odds ratio [OR] = 1.2), and informant perception of executive decline (OR = 1.6), increased the probability of a positive scan. Informant reports 3 years before scanning predicted Aβ PET outcome. Longitudinal increase of self-reported executive decline was predictive of Aβ in women (P = .003). Discussion: Subjective reports of cognitive decline are useful to predict Aβ and may improve recruitment strategies.The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/GN17/50300004 and the Alzheimer's Association and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa‐17‐519007). Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2017‐SGR‐892. Marc Suárez‐Calvet received funding from the European Union's Horizon 2020 Research and Innovation Program under the Marie Sklodowska‐Curie action grant agreement No 752310, and currently receives funding from Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation, and Universities (Juan de la Cierva Programme grant IJC2018‐037478‐I). Juan Domingo Gispert is supported by the Spanish Ministry of Science and Innovation (RYC‐2013‐13054). Oriol Grau‐Rivera is supported by the Spanish Ministry of Science, Innovation, and Universities (FJCI‐2017‐33437). ASV is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship (CP II 17/00029). Eider M. Arenaza‐Urquijo is supported by the Spanish Ministry of Science, Innovation and Universities–Spanish State Research Agency (RYC2018‐026053‐I). Carolina Minguillon was supported by the Spanish Ministry of Economy and Competitiveness (grant n° IEDI‐2016‐00690)

Cerebral amyloid-β load is associated with neurodegeneration and gliosis: Mediation by p-tau and interactions with risk factors early in the Alzheimer's continuum

Data de publicació electrònica: 04/03/2021Introduction: The association between cerebral amyloid-β accumulation and downstream CSF biomarkers is not fully understood, particularly in asymptomatic stages. Methods: In 318 cognitively unimpaired participants, we assessed the association between amyloid-β PET (Centiloid), and cerebrospinal fluid (CSF) biomarkers of several pathophysiological pathways. Interactions by Alzheimer's disease risk factors (age, sex and APOE-ε4), and the mediation effect of tau and neurodegeneration were also investigated. Results: Centiloids were positively associated with CSF biomarkers of tau pathology (p-tau), neurodegeneration (t-tau, NfL), synaptic dysfunction (neurogranin) and neuroinflammation (YKL-40, GFAP, sTREM2), presenting interactions with age (p-tau, t-tau, neurogranin) and sex (sTREM2, NfL). Most of these associations were mediated by p-tau, except for NfL. The interaction between sex and amyloid-β on sTREM2 and NfL was also tau-independent. Discussion: Early amyloid-β accumulation has a tau-independent effect on neurodegeneration and a tau-dependent effect on neuroinflammation. Besides, sex has a modifier effect on these associations independent of tau

Differential effects of sleep on brain structure and metabolism at the preclinical stages of AD

Data de publicació electrònica: 17-05-2023Introduction: Poor sleep quality is associated with cognitive outcomes in Alzheimer's disease (AD). We analyzed the associations between self-reported sleep quality and brain structure and function in cognitively unimpaired (CU) individuals. Methods: CU adults (N = 339) underwent structural magnetic resonance imaging, lumbar puncture, and the Pittsburgh Sleep Quality Index (PSQI) questionnaire. A subset (N = 295) performed [18F] fluorodeoxyglucose positron emission tomography scans. Voxel-wise associations with gray matter volumes (GMv) and cerebral glucose metabolism (CMRGlu) were performed including interactions with cerebrospinal fluid (CSF) AD biomarkers status. Results: Poorer sleep quality was associated with lower GMv and CMRGlu in the orbitofrontal and cingulate cortices independently of AD pathology. Self-reported sleep quality interacted with altered core AD CSF biomarkers in brain areas known to be affected in preclinical AD stages. Discussion: Poor sleep quality may impact brain structure and function independently from AD pathology. Alternatively, AD-related neurodegeneration in areas involved in sleep-wake regulation may induce or worsen sleep disturbances. Highlights Poor sleep impacts brain structure and function independent of Alzheimer's disease (AD) pathology. Poor sleep exacerbates brain changes observed in preclinical AD. Sleep is an appealing therapeutic strategy for preventing AD.This publication is part of the ALFA study (Alzheimer and Families). The authors would like to express their most sincere gratitude to the ALFA project participants and relatives, without whom this research would have not been possible. The authors thank Roche Diagnostics International Ltd. for providing the kits to measure CSF biomarkers and GE Healthcare for providing the doses for [18F]flutemetamol PET. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712 and #101053962), Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C, and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at UCL (UKDRI-1003). Collaborators of the ALFA Study are Müge Akinci, Annabella Beteta, Alba Cañas, Irene Cumplido, Carme Deulofeu, Ruth Dominguez, Maria Emilio, Karine Fauria, Sherezade Fuentes, Oriol Grau-Rivera, Laura Hernandez, Gema Huesa, Jordi Huguet, Eider M. Arenaza-Urquijo, Paula Marne, Tania Menchón, Carolina Minguillon, Eva M. Palacios, Eleni Palpatzis, Cleofé Peña-Gómez, Albina Polo, Sandra Pradas, Blanca Rodríguez-Fernández, Aleix Sala-Vila, Gemma Salvadó, Mahnaz Shekari, Anna Soteras, Laura Stankeviciute, Marc Vilanova, and Natalia Vilor-Tejedor. This work was supported by a grant from the Alzheimer's Association (2019-AARF-644568) awarded to O.G.-R. The ALFASleep study also receives funding from the Instituto de Salud Carlos III through the project PI19/00117 (co-funded by European Regional Development Fund; “A way to make Europe”) awarded to OG-R. The ALFA+ study is funded by the “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/GN17/50300004 and the Alzheimer's Association and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17-519007). O.G.-R. is supported by the Spanish Ministry of Science, Innovation and Universities (IJC2020-043417-I)

Centiloid cut-off values for optimal agreement between PET and CSF core AD biomarkers

Background: The Centiloid scale has been developed to standardize measurements of amyloid PET imaging. Reference cut-off values of this continuous measurement enable the consistent operationalization of decision-making for multicentre research studies and clinical trials. In this study, we aimed at deriving reference Centiloid thresholds that maximize the agreement against core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in two large independent cohorts. Methods: A total of 516 participants of the ALFA+ Study (N = 205) and ADNI (N = 311) underwent amyloid PET imaging ([18F]flutemetamol and [18F]florbetapir, respectively) and core AD CSF biomarker determination using Elecsys® tests. Tracer uptake was quantified in Centiloid units (CL). Optimal Centiloid cut-offs were sought that maximize the agreement between PET and dichotomous determinations based on CSF levels of Aβ42, tTau, pTau, and their ratios, using pre-established reference cut-off values. To this end, a receiver operating characteristic analysis (ROC) was conducted, and Centiloid cut-offs were calculated as those that maximized the Youden's J Index or the overall percentage agreement recorded. Results: All Centiloid cut-offs fell within the range of 25-35, except for CSF Aβ42 that rendered an optimal cut-off value of 12 CL. As expected, the agreement of tau/Aβ42 ratios was higher than that of CSF Aβ42. Centiloid cut-off robustness was confirmed even when established in an independent cohort and against variations of CSF cut-offs. Conclusions: A cut-off of 12 CL matches previously reported values derived against postmortem measures of AD neuropathology. Together with these previous findings, our results flag two relevant inflection points that would serve as boundary of different stages of amyloid pathology: one around 12 CL that marks the transition from the absence of pathology to subtle pathology and another one around 30 CL indicating the presence of established pathology. The derivation of robust and generalizable cut-offs for core AD biomarkers requires cohorts with adequate representation of intermediate levels.The research leading to these results has received funding from “la Caixa” Foundation (LCF/PR/GN17/10300004) and the Alzheimer’s Association and an international anonymous charity foundation through the the TriBEKa Imaging Platform project. JDG holds a ‘Ramón y Cajal’ fellowship (RYC-2013-13054). MS-C receives funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie action grant agreement No 752310. CM is supported by the Spanish Ministry of Economy and Competitiveness (grant n° IEDI-2016-00690). KB holds the Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences, and is supported by the Swedish Research Council (#2017-00915), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), and a grant (#ALFGBG-715986) from the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement