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BACKGROUND: Among plasma biomarkers for Alzheimer's disease (AD), pTau181 and pTau217 are the most promising. However, transition from research to routine clinical use will require confirmation of clinical performance in prospective cohorts and evaluation of cofounding factors. METHOD: pTau181 and pTau217 were quantified using, Quanterix and ALZpath, SIMOA assays in the well-characterised prospective multicentre BALTAZAR (Biomarker of AmyLoid pepTide and AlZheimer's diseAse Risk) cohort of participants with mild cognitive impairment (MCI). RESULTS: Among participants with MCI, 55% were Aß+ and 29% developed dementia due to AD. pTau181 and pTau217 were higher in the Aß+ population with fold change of 1.5 and 2.7, respectively. MCI that converted to AD also had higher levels than non-converters, with HRs of 1.38 (1.26 to 1.51) for pTau181 compared with 8.22 (5.45 to 12.39) for pTau217. The area under the curve for predicting Aß+ was 0.783 (95% CI 0.721 to 0.836; cut-point 2.75 pg/mL) for pTau181 and 0.914 (95% CI 0.868 to 0.948; cut-point 0.44 pg/mL) for pTau217. The high predictive power of pTau217 was not improved by adding age, sex and apolipoprotein E ε4 (APOEε4) status, in a logistic model. Age, APOEε4 and renal dysfunction were associated with pTau levels, but the clinical performance of pTau217 was only marginally altered by these factors. Using a two cut-point approach, a 95% positive predictive value for Aß+ corresponded to pTau217 >0.8 pg/mL and a 95% negative predictive value at <0.23 pg/mL. At these two cut-points, the percentages of MCI conversion were 56.8% and 9.7%, respectively, while the annual rates of decline in Mini-Mental State Examination were -2.32 versus -0.65. CONCLUSIONS: Plasma pTau217 and pTau181 both correlate with AD, but the fold change in pTau217 makes it better to diagnose cerebral amyloidosis, and predict cognitive decline and conversion to AD dementia.
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PURPOSE OF REVIEW: Dementia is a growing concern and underscores the urgent need for effective preventive measures targeting modifiable risk factors. Nutrition is a key player in the onset and progression of inflammation and cognitive decline. This review provides a comprehensive overview of the effects of different dietary patterns, vitamins and nutrients for preventing cognitive decline, mainly among healthy individuals and those with mild cognitive impairment. RECENT FINDINGS: The Mediterranean diet, omega-3 long-chain polyunsaturated fatty acids and B vitamins are the most investigated, with evidence supporting protection against cognitive decline among older adults varying across studies. More recent interventions examined in this review, such as MIND Diet, are promising with positive results, but further research is needed to conclusively establish their efficacy. It is also crucial to consider complete lifestyle as physical activity for preventing cognitive decline. SUMMARY: Definitive conclusions are difficult to draw. Future studies should adopt a comprehensive approach and focus on multinutrient strategies and whole diets.
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Disfunção Cognitiva , Dieta Mediterrânea , Humanos , Idoso , Disfunção Cognitiva/prevenção & controle , Estado Nutricional , Fatores de Risco , Vitaminas , CogniçãoRESUMO
The majority of microplastics (MPs) found in the environment originate from plastic fragmentation occurring in the environment and are influenced by environmental factors such as UV irradiation and biotic interactions. However, the effects of river drying on plastic fragmentation remain unknown, despite the global prevalence of watercourses experiencing flow intermittence. This study investigates, through laboratory experiments, the coupled effects of drying duration and UV irradiation on PVC film fragmentation induced by artificial mechanical abrasion. This study shows that PVC film fragmentation increases with drying duration through an increase in the abundance and size of formed MPs as well as mass loss from the initial plastic item, with significant differences for drying durations >50% of the experiment duration. The average abundance of formed MPs in treatments exposed to severe drying duration was almost two times higher than in treatments nonexposed to drying. Based on these results, we developed as a proof of concept an Intermittence-Based Plastic Fragmentation Index that may provide insights into plastic fragmentation occurring in river catchments experiencing large hydrological variability. The present study suggests that flow intermittence occurring in rivers and streams can lead to increasing plastic fragmentation, unraveling new insights into plastic pollution in freshwater systems.
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Microplásticos , Cloreto de Polivinila , Rios , Rios/química , Cloreto de Polivinila/química , Poluentes Químicos da Água , Raios Ultravioleta , Monitoramento Ambiental , DessecaçãoRESUMO
INTRODUCTION: We investigated the link between habitual caffeine intake with memory impairments and cerebrospinal fluid (CSF) biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients. METHODS: MCI (N = 147) and AD (N = 116) patients of the Biomarker of AmyLoid pepTide and AlZheimer's diseAse Risk (BALTAZAR) cohort reported their caffeine intake at inclusion using a dedicated survey. Associations of caffeine consumption with memory impairments and CSF biomarkers (tau, p-tau181, amyloid beta 1-42 [Aß1-42], Aß1-40) were analyzed using logistic and analysis of covariance models. RESULTS: Adjusted on Apolipoprotein E (APOE ε4), age, sex, education level, and tobacco, lower caffeine consumption was associated with higher risk to be amnestic (OR: 2.49 [95% CI: 1.13 to 5.46]; p = 0.023) and lower CSF Aß1-42 (p = 0.047), Aß1-42/Aß1-40 (p = 0.040), and Aß1-42/p-tau181 (p = 0.020) in the whole cohort. DISCUSSION: Data support the beneficial effect of caffeine consumption to memory impairments and CSF amyloid markers in MCI and AD patients. HIGHLIGHTS: We studied the impact of caffeine consumption in the BALTAZAR cohort. Low caffeine intake is associated with higher risk of being amnestic in MCI/AD patients. Caffeine intake is associated with CSF biomarkers in AD patients.
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BACKGROUND: Among blood biomarkers, phospho-tau181 (pTau181) is one of the most efficient in detecting Alzheimer disease across its continuum. However, transition from research to routine clinical use will require confirmation of clinical performance in prospective cohorts and evaluation of cofounding factors. METHODS: Here we tested the Lumipulse assay for plasma pTau181 in mild cognitive impairment (MCI) participants from the Baltazar prospective cohort. We compared the performance of this assay to the corresponding Simoa assay for the prediction of conversion to dementia. We also evaluated the association with various routine blood parameters indicative of comorbidities. RESULTS: Lumipulse and Simoa gave similar results overall, with hazard ratios for conversion to dementia of 3.48 (95% CI, 2.23-5.45) and 3.70 (95%CI, 2.39-5.87), respectively. However, the 2 tests differ somewhat in terms of the patients identified, suggesting that their use may be complementary. When combined with age, sex, and apolipoprotein E (APOE)ε4 status, areas under the curves for conversion detection were 0.736 (95% CI, 0.682-0.791) for Lumipulse and 0.733 (95% CI, 0.679-0.788) for Simoa. Plasma pTau181 was independently associated with renal dysfunction (assessed by creatinine and glomerular filtration) for both assays. Cardiovascular factors (adiponectin and cholesterol), nutritional, and inflammatory markers (total protein content, C-reactive protein) also impacted plasma pTau181 concentration, although more so with the Simoa than with the Lumipulse assay. CONCLUSIONS: Plasma pTau181 measured using the fully automated Lumipulse assay performs as well as the Simoa assay for detecting conversion to dementia of MCI patients within 3 years and Lumipulse is less affected by comorbidities. This study suggests a pathway to routine noninvasive in vitro diagnosis-approved testing to contribute to the management of Alzheimer disease. CLINICALTRIALS.GOV REGISTRATION NUMBER: NCT01315639.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Estudos Prospectivos , Plasma , Adiponectina , Disfunção Cognitiva/diagnósticoRESUMO
OBJECTIVES: Plasma P-tau181 is an increasingly established diagnostic marker for Alzheimer's disease (AD). Further validation in prospective cohorts is still needed, as well as the study of confounding factors that could influence its blood level. METHODS: This study is ancillary to the prospective multicentre Biomarker of AmyLoid pepTide and AlZheimer's diseAse Risk cohort that enrolled participants with mild cognitive impairment (MCI) who were examined for conversion to dementia for up to 3 years. Plasma Ptau-181 was measured using the ultrasensitive Quanterix HD-X assay. RESULTS: Among 476 MCI participants, 67% were amyloid positive (Aß+) at baseline and 30% developed dementia. Plasma P-tau181 was higher in the Aß+ population (3.9 (SD 1.4) vs 2.6 (SD 1.4) pg/mL) and in MCI that converted to dementia (3.8 (SD 1.5) vs 2.9 (SD 1.4) pg/mL). The addition of plasma P-tau181 to a logistic regression model combining age, sex, APOEε4 status and Mini Mental State Examination improved predictive performance (areas under the curve 0.691-0.744 for conversion and 0.786-0.849 for Aß+). The Kaplan-Meier curve of conversion to dementia, according to the tertiles of plasma P-tau181, revealed a significant predictive value (Log rank p<0.0001) with an HR of 3.8 (95% CI 2.5 to 5.8). In addition, patients with plasma P-Tau(181) ≤2.32 pg/mL had a conversion rate of less than 20% over a 3-year period. Using a linear regression approach, chronic kidney disease, creatinine and estimated glomerular filtration rate were independently associated with plasma P-tau181 concentrations. CONCLUSIONS: Plasma P-tau181 effectively detects Aß+ status and conversion to dementia, confirming the value of this blood biomarker for the management of AD. However, renal function significantly modifies its levels and may thus induce diagnostic errors if not taken into account.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/diagnóstico , Proteínas tau , Peptídeos beta-Amiloides , Estudos Prospectivos , Disfunção Cognitiva/diagnóstico , Biomarcadores , Rim/fisiologiaRESUMO
BACKGROUND: The incidence of sepsis increases significantly with age, including a high incidence of bacterial infection in the old adults. Eosinopenia and the CIBLE score have been proposed in critically ill adults and in internal medicine wards. This study aimed to assess whether a low eosinophil count was associated with acute bacterial infection among hospitalized older adults, and to find the most efficient eosinophil count cut-off to differentiate acute bacterial infection from other inflammatory states. METHODS: This was a prospective study from July 2020 to July 2022 in geriatric wards of the University Paul Brousse Hospital (Villejuif, France) including patients aged of 75 y/o or over suffering from fever or biological inflammation. Acute bacterial infection was assessed using biological identification and/or clinical and radiological data. RESULTS: A total of 156 patients were included. Eighty-two (53%) patients suffered from acute bacterial infection (mean age (SD) 88.7 (5.9)). Low eosinophil count was independently associated with acute bacterial infection: OR [CI95%] 3.03 [1.04-9.37] and 6.08 [2.42-16.5] for eosinophil count 0-0.07 G/L and 0.07-0.172 G/L respectively (vs. eosinophil count > 0.172 G/L). Specificity and sensitivity for eosinophil count < 0.01 G/L and CIBLE score were 84%-49% and 72%-62%, respectively with equivalent AUCs (0.66 and 0.67). CONCLUSION: Eosinophil count < 0.01 G/L is a simple, routinely used and inexpensive tool which can easily participate in antibiotic decisions for older adults. Further studies are needed to assess clinical benefits. TRIAL REGISTRATION: The study was registered at Clinical trial.gov (NCT04363138-23/04/2020).
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Infecções Bacterianas , Infecções , Humanos , Idoso , Eosinófilos , Estudos Prospectivos , Contagem de Leucócitos , Infecções Bacterianas/complicações , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/epidemiologiaRESUMO
BACKGROUND: In older adults, physical activity (PA) is important in maintaining physical performance. Data on the effectiveness of public open-access community-based programs on physical performance and fall prevention are scarce. METHODS: Prospective observational controlled study in community centers providing an open-access public prevention program. Retirees aged ≥60 years who chose to participate in weekly PA workshops for 3 months were compared to those who chose the cognitive stimulation (CS) workshops. Collected data: handgrip strength, five times sit-to-stand, single-leg stance, Timed Up and Go tests, gait speed, short physical performance battery (SPPB) and frailty status at baseline (M0) and at 3 months (M3). The proportion of participants reporting a history of falls was assessed at baseline and using follow-up telephone interviews (F-Up). RESULTS: Two hundred eighty-eight participants (age 73.8 years, 87% women) were included. The sit-to-stand test, single-leg stance and SPPB scores improved significantly between M0 and M3 in both groups. A greater SPPB increase was observed in the PA than in the CS group (+0.39 vs. +0.32 points, P = 0.02) after adjustment for age, sex, number of sessions attended, fall history and SPPB at baseline. During F-Up (median 22 months), the proportion of participants reporting at least one fall decreased from 55% to 31% (P = 0.01) in the PA group and from 27% to 19% (P = 0.12) in the CS group. CONCLUSION: In a public open-access community-based program participants improved physical performance and reduced fall incidence when participating in the PA or the CS workshops. Older adults may benefit most from multifaceted prevention programs.
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Exercício Físico , Força da Mão , Humanos , Feminino , Idoso , Masculino , Exercício Físico/psicologia , Velocidade de Caminhada/fisiologia , Desempenho Físico FuncionalRESUMO
Neurofilament light chain (NfL) is a potential diagnostic and prognostic plasma biomarker for numerous neurological diseases including Alzheimer's disease (AD). In this study, we investigated the relationship between baseline plasma concentration of Nfl and Mild Cognitive Impairment in participants who did and did not have a clinically determined diagnosis of dementia by the end of the three-year study. Additionally, we explored the connection between baseline plasma concentration of NfL and AD dementia patients, considering their demographics, clinical features, and cognitive profiles. A total of 350 participants from the Biomarker of AmyLoid pepTide and AlZheimer's diseAse Risk (BALTAZAR) multicenter prospective study were investigated: 161 AD dementia participants and 189 MCI participants (of which 141 had amnestic MCI and 48 non-amnestic MCI). Plasma biomarkers were measured at baseline and the progression of clinical and cognitive profiles was followed over the three years of follow-up. Baseline plasma NfL concentration increased across the Alzheimer's disease continuum with a mean NfL value of 17.1 ng/mL [SD = 6.1] in non-amnestic MCI, 20.7 ng/mL [SD = 12.0] in amnestic MCI, and 23.1 ng/mL [SD = 22.7] in AD dementia patients. Plasma NfL concentration correlated with age, body mass index (BMI), and global cognitive performance and decline, as measured by the Mini-Mental State Examination (MMSE). MMSE scores decreased in parallel with increasing plasma NfL concentration, independently of age and BMI. However, NfL concentration did not predict MCI participants' conversion to dementia within three years. Discussion: Baseline plasma NfL concentration is associated with cognitive status along the AD continuum, suggesting its usefulness as a potential informative biomarker for cognitive decline follow-up in patients.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/diagnóstico , Estudos Prospectivos , Filamentos Intermediários , Proteínas de Neurofilamentos , Disfunção Cognitiva/diagnóstico , Biomarcadores , Peptídeos beta-Amiloides , Progressão da Doença , Proteínas tauRESUMO
BACKGROUND: Road safety is a major issue among seniors. Potentially Driver-Impairing (PDI) drugs are known to increase the risk of car accident. The aim of this cross-sectional study was to describe PDI-drug consumption among older drivers and determine associated factors. METHODS: The S.AGES cohort is a French non-interventional real-life prospective study of 3700 community-dwelling participants aged ≥65 years old, suffering from type 2 diabetes (T2DM), chronic pain or atrial fibrillation (AF). Baseline data of drivers with known treatment (n = 1783) were used for the analyses. PDI drugs were defined according to the French classification. RESULTS: One thousand seven hundred eighty-three drivers were included (66% males; mean age 76 (Standard deviation = 5.78) years old). 21% (n = 373) took PDI drugs, 64% of which took only one (n = 239). The most frequent PDI drugs were: Zolpidem (11%; n = 60); Zopiclone (8%; n = 45); Bromazepam (8%; n = 44); Tramadol (7%; n = 39); Pregabalin (6%; n = 31). Drivers taking PDI drugs had more often chronic pain (OR [95% CI] = 2.30 [1.54-3.46]), history of depressive disorder (4.28 [3.00-6.14]) and polypharmacy (taking at least 5 different medications; 4.32 [2.97-6.41]), and less often T2DM (0.54 [0.37-0.79]), and AF (0.48 [0.32-0.71]). Conversely, they had a lower Activities of Daily Living score (0.34 [0.17-0.68]). CONCLUSIONS: The rate of aged drivers in the S.AGES cohort taking PDI drugs is concerning and highlights the need to carefully assess and reassess PDI-drug prescriptions in this population, particularly hypnotics, anxiolytics and opioids. TRIAL REGISTRATION: ClinicalTrials.gov NCT01065909 (First posted: February 9th, 2010).
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Condução de Veículo , Diabetes Mellitus Tipo 2 , Preparações Farmacêuticas , Acidentes de Trânsito , Atividades Cotidianas , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Estudos ProspectivosRESUMO
INTRODUCTION: Blood-based biomarkers are the next challenge for Alzheimer's disease (AD) diagnosis and prognosis. METHODS: Mild cognitive impairment (MCI) participants (N = 485) of the BALTAZAR study, a large-scale longitudinal multicenter cohort, were followed-up for 3 years. A total of 165 of them converted to dementia (95% AD). Associations of conversion and plasma amyloid beta (Aß)1-42 , Aß1-40 , Aß1-42 /Aß1-40 ratio were analyzed with logistic and Cox models. RESULTS: Converters to dementia had lower level of plasma Aß1-42 (37.1 pg/mL [12.5] vs. 39.2 [11.1] , P value = .03) and lower Aß1-42 /Aß1-40 ratio than non-converters (0.148 [0.125] vs. 0.154 [0.076], P value = .02). MCI participants in the highest quartile of Aß1-42 /Aß1-40 ratio (>0.169) had a significant lower risk of conversion (hazard ratio adjusted for age, sex, education, apolipoprotein E ε4, hippocampus atrophy = 0.52 (95% confidence interval [0.31-0.86], P value = .01). DISCUSSION: In this large cohort of MCI subjects we identified a threshold for plasma Aß1-42 /Aß1-40 ratio that may detect patients with a low risk of conversion to dementia within 3 years.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Peptídeos beta-Amiloides , Disfunção Cognitiva/diagnóstico , Doença de Alzheimer/diagnóstico , Apolipoproteína E4 , Biomarcadores , Fragmentos de Peptídeos , Proteínas tau , Progressão da DoençaRESUMO
MAIN CONCLUSION: A synthetic peptide from the C-terminal end of C4-phosphoenolpyruvate carboxylase is implicated in the proteolysis of the enzyme, and Glc-6P or phosphorylation of the enzyme modulate this effect. Phosphoenolpyruvate carboxylase (PEPC) is a cytosolic, homotetrameric enzyme that performs a variety of functions in plants. Among them, it is primarily responsible for CO2 fixation in the C4 photosynthesis pathway (C4-PEPC). Here we show that proteolysis of C4-PEPC by cathepsin proteases present in a semi-purified PEPC fraction was enhanced by the presence of a synthetic peptide containing the last 19 amino acids from the C-terminal end of the PEPC subunit (pC19). Threonine (Thr)944 and Thr948 in the peptide are important requirements for the pC19 effect. C4-PEPC proteolysis in the presence of pC19 was prevented by the PEPC allosteric effector glucose 6-phosphate (Glc-6P) and by phosphorylation of the enzyme. The role of these elements in the regulation of PEPC proteolysis is discussed in relation to the physiological context.
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Fosfoenolpiruvato Carboxilase , Sorghum , Glucose-6-Fosfato , Peptídeos , Fosfoenolpiruvato Carboxilase/metabolismo , Fosforilação , Fotossíntese , Proteólise , Sorghum/metabolismoRESUMO
BACKGROUND: Yellow fever vaccine (YFV) is not advised for multiple sclerosis (MS) patients because of the potential risk of post-vaccine relapses. OBJECTIVE: To assess the risk of relapsing-remitting multiple sclerosis (RR-MS) worsening after YFV. METHODS: Non-interventional observational retrospective, exposed/non-exposed cohort study nested in the French national cohort including MS. RESULTS: 128 RR-MS were included. The 1-year annualized relapse rate (ARR) following YFV did not differ between exposed: 0.219 (0.420) and non-exposed subjects: 0.208 (0.521) (p = 0.92). Time to first relapse was not different between groups (adjusted hazard ratio (HR) = 1.33; 95% confidence interval (CI) = 0.53-3.30, p = 0.54). CONCLUSION: These results suggest that YFV does not worsen the course of RR-MS.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Febre Amarela , Estudos de Coortes , Humanos , Esclerose Múltipla/epidemiologia , Esclerose Múltipla Recidivante-Remitente/epidemiologia , Estudos Retrospectivos , Vacinação/efeitos adversos , Febre Amarela/epidemiologia , Febre Amarela/prevenção & controleRESUMO
Safety assessment of chemicals and products in the European Union (EU) is based on decades of practice using primarily animal toxicity studies to model hazardous effects in humans. Nevertheless, there has been a long-standing ethical concern about using experimental animals. In addition, animal models may fail to predict adverse effects in humans. This has provided a strong motivation to develop and use new approach methodologies and other alternative sources of evidence. A key challenge for this is integration of evidence from different sources. This paper is a call for action with regard to development, validation, and implementation of modern safety assessment approaches for human health assessment by means of focused applied research and development with three strands: (a) to improve screening and priority setting, (b) to enhance and partially replace animal studies under the current regulatory schemes and eventually (c) to fully replace animal studies, while achieving at least the same level of protection. For this gradual but systematic replacement of animal studies, a long-term concerted and coordinated effort with clear goals is needed at EU level, as a societal and political choice, to plan and motivate research and innovation in regulatory safety assessment.
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Alternativas aos Testes com Animais , Substâncias Perigosas/toxicidade , Testes de Toxicidade/métodos , União Europeia , Regulamentação GovernamentalRESUMO
BACKGROUND: To evaluate the prevalence and management of heart failure (HF) in very old patients in geriatric settings. METHODS: Members of the French Society of Geriatrics and Gerontology throughout France were invited to participate in a point prevalence survey and to include all patients ≥80 years old, hospitalized in geriatric settings, with HF (stable or decompensated) on June 18, 2012. General characteristics, presence of comorbidities, blood tests and medications were recorded. RESULTS: Among 7,197 patients in geriatric institution, prevalence of HF was 20.5% (n = 1,478): (27% in acute care, 24.2% in rehabilitation care and 18% in nursing home). Mean age was 88.2 (SD = 5.2) and Charlson co morbidity score was high (8.49 (SD = 2.21)). Left ventricular ejection fraction (LVEF) was available in 770 (52%) patients: 536 (69.6%) had a preserved LVEF (≥ 50%), 120 (15.6%) a reduced LVEF (< 40%), and 114 (14.8%) a midrange LVEF (40-49%). Prescription of recommended HF drugs was low: 42.6% (629) used Angiotensin Converting Enzyme Inhibitors (ACEI) or Angiotensin Receptor Blockers (ARBs), 48.0% (709) ß-blockers, and 21.9% (324) ACEI or ARB with ß-blockers, even in reduced LVEF. In multivariate analysis ACEI or ARBs were more often used in patients with myocardial infarction (1.36 (1.04-1.78)), stroke (1.42 (1.06-1.91)), and diabetes (1.54 (1.14-2.06)). ß blockers were more likely used in patients with myocardial infarction (2.06 (1.54-2.76)) and atrial fibrillation (1.70 (1.28-2.28)). CONCLUSION: In this large very old population, prevalence of HF was high. Recommended HF drugs were underused even in reduced LVEF. These results indicate that management of HF in geriatric settings can still be improved.
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Gerenciamento Clínico , Serviços de Saúde para Idosos/tendências , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/terapia , Inquéritos e Questionários , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Feminino , França/epidemiologia , Insuficiência Cardíaca/diagnóstico , Humanos , Masculino , Sociedades Médicas/tendências , Volume Sistólico/efeitos dos fármacos , Volume Sistólico/fisiologia , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologiaRESUMO
Arabidopsis thaliana SNF1-related-kinase 1 (SnRK1)-activating kinase 1 (AtSnAK1) and AtSnAK2 have been shown to phosphorylate in vitro and activate the energy signalling integrator, SnRK1. To clarify this signalling cascade in planta, a genetic- and molecular-based approach was developed. Homozygous single AtSnAK1 and AtSnAK2 T-DNA insertional mutants did not display an apparent phenotype. Crossing of the single mutants did not allow the isolation of double-mutant plants, whereas self-pollinating the S1-/- S2+/- sesquimutant specifically gave approximatively 22% individuals in their offspring that, when rescued on sugar-supplemented media in vitro, were shown to be AtSnAK1 AtSnAK2 double mutants. Interestingly, this was not obtained in the case of the other sesquimutant, S1+/- S2-/-. Although reduced in size, the double mutant had the capacity to produce flowers, but not seeds. Immunological characterization established the T-loop of the SnRK1 catalytic subunit to be non-phosphorylated in the absence of both SnAKs. When the double mutant was complemented with a DNA construct containing an AtSnAK2 open reading frame driven by its own promoter, a normal phenotype was restored. Therefore, wild-type plant growth and development is dependent on the presence of SnAK in vivo, and this is correlated with SnRK1 phosphorylation. These data show that both SnAKs are kinases phosphorylating SnRK1, and thereby they contribute to energy signalling in planta.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Regulação da Expressão Gênica de Plantas , Fases de Leitura Aberta/genética , Fosforilação/genética , Fosforilação/fisiologia , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
INTRODUCTION: Diagnostic relevance of plasma amyloid ß (Aß) for Alzheimer's disease (AD) process yields conflicting results. The objective of the study was to assess plasma levels of Aß42 and Aß40 in amnestic mild cognitive impairment (MCI), nonamnestic MCI, and AD patients and to investigate relationships between peripheral and central biomarkers. METHODS: One thousand forty participants (417 amnestic MCI, 122 nonamnestic MCI, and 501 AD) from the Biomarker of AmyLoïd pepTide and AlZheimer's diseAse Risk multicenter prospective study with cognition, plasma, cerebrospinal fluid (CSF), and magnetic resonance imaging assessments were included. RESULTS: Plasma Aß1-42 and Aß1-40 were lower in AD (36.9 [11.7] and 263 [80] pg/mL) than in amnestic MCI (38.2 [11.9] and 269 [68] pg/mL) than in nonamnestic MCI (39.7 [10.5] and 272 [52] pg/mL), respectively (P = .01 for overall difference between groups for Aß1-42 and P = .04 for Aß1-40). Globally, plasma Aß1-42 correlated with age, Mini-Mental State Examination, and APOE ε4 allele. Plasma Aß1-42 correlated with all CSF biomarkers in MCI but only with CSF Aß42 in AD. DISCUSSION: Plasma Aß was associated with cognitive status and CSF biomarkers, suggesting the interest of plasma amyloid biomarkers for diagnosis purpose.
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Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/sangue , Biomarcadores , Disfunção Cognitiva/sangue , Disfunção Cognitiva/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência/estatística & dados numéricos , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
There is growing evidence that sub-structures of the brain scale allometrically to total brain size, that is, in a non-proportional and non-linear way. Here, scaling of different volumes of interest (VOI) to intra-cranial volume (ICV) was examined. It was assessed whether scaling was allometric or isometric and whether scaling coefficients significantly differed from each other. We also tested to what extent allometric scaling of VOI was introduced by the automated segmentation technique. Furthermore, reproducibility of allometric scaling was studied different age groups and study populations. Study samples included samples of cognitively healthy adults from the community-based Age Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik Study) (N = 3,883), the Coronary Artery Risk Development in Young Adults Study (CARDIA) (N =709), and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 180). Data encompassed participants with different age, ethnicity, risk factor profile, and ICV and VOI obtained with different automated MRI segmentation techniques. Our analysis showed that (1) allometric scaling is a trait of all parts of the brain, (2) scaling of neo-cortical white matter, neo-cortical gray matter, and deep gray matter structures including the cerebellum are significantly different from each other, and (3) allometric scaling of brain structures cannot solely be explained by age-associated atrophy, sex, ethnicity, or a systematic bias from study-specific segmentation algorithm, but appears to be a true feature of brain geometry. Hum Brain Mapp 38:151-164, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Envelhecimento , Algoritmos , Mapeamento Encefálico , Encéfalo/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/epidemiologia , Encéfalo/diagnóstico por imagem , Planejamento em Saúde Comunitária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/patologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Países Baixos/epidemiologia , Reprodutibilidade dos Testes , Fatores SexuaisRESUMO
OBJECTIVE: To examine older adults' performance on a newly developed tablet-PC-based cancellation test (e-CT) and to study its psychometric properties. METHODS: 94 older adults with normal cognitive functioning were recruited. The effects of age, education, sex, and experience with computer-based devices on the e-CT were examined. Construct validity was tested by correlating the e-CT with established measures of executive functions (EF) and episodic memory. Correlation coefficients were used to assess short-term test-retest reliablity. RESULTS: The mean age of participants was 74.6 (SD: 7.3) years and 78% were women. Sixty-nine percent had higher education level (> high school) and 76% used computer-based devices daily. The correct cancellations (CC) on the e-CT ranged from 18 to 56, with a mean (SD) of 40.3 (5.7). The CC was inversely correlated with advancing age (rs = -0.59, N = 94, p <0.001) and positively associated with higher education level (U(94) = 646.5, p = 0.02). No relationship was observed between the e-CT and sex or computer-based device experience. In multivariate analysis, only age remained significantly associated with CC (ß = -0.46, SE = 0.07, t = -6.47, df = 93, p <0.001). The e-CT correlated significantly with most of measures of EF. Highest correlations were found between the e-CT and the K-T test, a paper-and-pencil cancellation test (rs = 0.63, N = 90, p <0.001) and TMT-B (rs = -0.41, N = 85, p <0.001). The e-CT did not correlate with the RL-RI 16 episodic memory test. The correlation between the first and second e-CT indicated good reliability (rs = 0.89, N = 13, p <0.001). CONCLUSIONS: Results suggested that e-CT has good psychometric properties and may be useful for assessing EF in older adults.