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BACKGROUND: Atrial fibrillation (AF) is a risk factor for cognitive impairment and dementia in patients with stroke history. However, the association between AF and cognitive impairment in broader populations is less clear. OBJECTIVE: To systematically review and quantitatively synthesize the existing evidence regarding the association of AF with cognitive impairment of any severity and etiology and dementia. METHODS: Medline, Scopus, and Cochrane Central were searched in order to identify studies investigating the association between AF and cognitive impairment (or dementia) cross-sectionally and longitudinally. Studies encompassing and analyzing exclusively patients with stroke history were excluded. A random-effects model meta-analysis was conducted. Potential sources of between-study heterogeneity were investigated via subgroup and meta-regression analyses. Sensitivity analyses including only studies reporting data on stroke-free patients, vascular dementia, and Alzheimer's disease were performed. RESULTS: In total, 43 studies were included. In the pooled analysis, AF was significantly associated with dementia (adjusted OR, 1.6; 95% CI, 1.3 to 2.1; I2, 31%) and the combined endpoint of cognitive impairment or dementia (pooled adjusted OR, 1.5; 95% CI, 1.4 to 1.8; I2, 34%). The results were significant, even when studies including only stroke-free patients were pooled together (unadjusted OR, 2.2; 95% CI, 1.4 to 3.5; I2, 96%), but the heterogeneity rates were high. AF was significantly associated with increased risk of both vascular (adjusted OR, 1.7; 95% CI, 1.2 to 2.3; I2, 43%) and Alzheimer's dementia (adjusted HR, 1.4; 95% CI, 1.2 to 1.6; I2, 42%). CONCLUSION: AF increases the risk of cognitive impairment, all-cause dementia, vascular dementia, and Alzheimer's disease. Future studies should employ interventions that may delay or even prevent cognitive decline in AF patients.
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Enfermedad de Alzheimer , Fibrilación Atrial , Disfunción Cognitiva , Demencia Vascular , Demencia , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/epidemiología , Fibrilación Atrial/complicaciones , Fibrilación Atrial/epidemiología , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Demencia/diagnóstico , Demencia/epidemiología , Demencia/etiología , Demencia Vascular/diagnóstico , Demencia Vascular/epidemiología , Demencia Vascular/etiología , HumanosRESUMEN
INTRODUCTION: Improvement of cognitive function may be desirable for healthy individuals and clinically beneficial for those with cognitive impairment such as from Alzheimer's disease (AD) or mild cognitive impairment (MCI). The aim of this systematic review is to investigate the cognitive effects of oral saffron intake, in patients with MCI/AD and/or in non-demented individuals, by following the PRISMA guidelines. METHODS: We performed a literature search on MedLine, Cochrane library, and ClinicalTrials.gov to identify randomized controlled trials (RCTs) investigating the effects of oral saffron administration in patients with MCI/AD and/or in non-demented individuals. RESULTS: Five studies (enrolling 325 individuals) met our inclusion criteria. Four studies included patients with MCI/AD, and one study included cognitively normal individuals. Saffron was well-tolerated in all groups. Regarding cognitively impaired patients, scores on Alzheimer's Disease Assessment Scale-cognitive subscale or Mini mental state examination were significantly better when saffron was compared with placebo and did not differ significantly when saffron was compared with donepezil or memantine. Saffron effects on functional status were similar with its effects on cognition. CONCLUSIONS: Saffron was shown to be equally effective to common symptomatic drugs for MCI/AD and resulted in no difference in the incidence of side effects, when compared with placebo or drugs. The promising results should be seen cautiously, since the evidence was derived from studies with potentially high risk of bias (ROB). RCTs with larger sample sizes and low ROB are required to definitively assess the potential role of saffron as an MCI/AD treatment.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Crocus , Enfermedad de Alzheimer/tratamiento farmacológico , Cognición , Disfunción Cognitiva/tratamiento farmacológico , Donepezilo , HumanosRESUMEN
BACKGROUND: Keeping up to date with the latest medical information using Web-based resources has been sparsely described, and a comprehensive up-to-date review is needed. OBJECTIVES: To summarise the Web-based 'channels' that may assist the actors of the health care system (clinicians, medical researchers and students) to keep up to date with medical information. METHODS: We searched PubMed and Scopus for English language articles published between January 1990 and February 2019 that investigated ways for keeping up with medical information. We used the results from our search and relevant information from other sources to conduct a narrative synthesis. RESULTS: We found that resources that push information (e.g. web alerts, medical newsletters, listservs), resources that rely on the active information seeking (e.g. access to health librarians and electronic databases, podcasts, mobile apps), collaborative resources (e.g. web conferences, online journal clubs, web social media) and resources that synthesise information (e.g. bibliometrics, living systematic reviews) can contribute in keeping up with new findings and can enhance evidence-based medicine. Clinicians, medical researchers and students can benefit from the proper use of such Internet-based technological innovations. CONCLUSION: Internet provides many resources that can help the actors of the health care system stay up to date with the latest scientific findings.
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Intercambio de Información en Salud/tendencias , Recursos en Salud/tendencias , Internet , Bibliometría , HumanosRESUMEN
Background and Purpose- Acute stroke treatment is challenging, and stroke remains a major cause of death and disability. The purpose of this meta-analysis is to investigate the effects of postacute stroke intravenous administration of the neuroprotectant magnesium sulfate (MgSO4) on global outcome, functional outcome, and mortality 90 days poststroke (ischemic and nonischemic). Methods- We searched in Pubmed, Science Direct, CENTRAL, and ClinicalTrials.gov, up to November 11, 2017, and we conducted a systematic review and meta-analysis of randomized controlled trials. We synthesized results by using random-effects model, weighted mean differences, standardized mean differences, and odds ratios. Results- Seven randomized controlled trials (4347 patients) met our criteria. Compared with placebo, treatment did not improve functional outcome defined as Barthel Index >60 (odds ratio =1.05; 95% CI, 0.92-1.19) and >95 (odds ratio =0.95; 95% CI, 0.76-1.20), 90 days poststroke. It also did not improve global outcome measured with modified Rankin Scale (standardized mean difference =-0.01; 95% CI, -0.12 to 0.10), 90 days poststroke. In an additional subgroup meta-analysis that exclusively included ischemic stroke patients, intravenous MgSO4 resulted in lower modified Rankin Scale score (improved global outcome; weighted mean difference =-0.96; 95% CI, -1.34 to -0.58; I2=0%], 90 days poststroke. Finally, mortality stayed unaltered (odds ratio =1.10; 95% CI, 0.94-1.29). Conclusions- The findings of our meta-analysis showed that intravenous MgSO4 generally did not improve global/functional outcomes and mortality at 90 days after stroke (combined ischemic stroke and nonischemic stroke). The finding of favorable neurological outcome, selectively in ischemic stroke patients, should be viewed with extreme caution given the limited number of patients included in this subgroup meta-analysis.
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Isquemia Encefálica/tratamiento farmacológico , Hemorragias Intracraneales/tratamiento farmacológico , Sulfato de Magnesio/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Administración Intravenosa , Humanos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). The pathologic hallmarks of the disease are the loss of dopaminergic neurons of substantia nigra pars compacta and the presence of intraneuronal alpha synuclein (a-syn) aggregates. Clinical features of PD include motor symptoms such as bradykinesia, rigidity, tremors, postural instability, and gait impairment, and non-motor symptoms such as constipation, orthostatic hypotension, REM sleep disorder, depression and dementia. Currently, there is no disease-modifying therapy for PD. Several human studies have shown that exercise reduces progression of motor symptoms, improves performance on cognitive tasks, and slows functional deterioration. However, regular exercise may not always be feasible in PD patients. Irisin is an exercise-induced myokine involved in metabolism modulation and body fat reduction, but it also crosses the blood-brain barrier and may mediate some of the benefits of exercise in brain function. Recent evidence has shown that irisin could be therapeutically promising in PD as an "exercise-mimicking" intervention. Exogenous irisin administration decreases brain a-syn pathology and loss of dopaminergic neurons, while it improves motor outcomes in preclinical models. Several other neurodegenerative disorders such as AD share common underlying pathogenetic mechanisms with PD such as protein misfolding and aggregation, neuroinflammation, brain metabolic abnormalities, and neuronal loss. Therefore, investigation of irisin as a disease-modifying therapy could be promising for PD and other neurodegenerative disorders including AD.
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Sodium-glucose cotransporter-2 inhibitors (SGLT2is), such as empagliflozin, lower blood glucose in type 2 diabetes mellitus and improve cardiorenal outcomes regardless of diabetes presence. Whether SGLT2is exert any effects on the brain's metabolism has not been studied. We conducted a single-arm clinical trial to investigate the effects of once daily administration of oral empagliflozin (25 mg) for 14 days on systemic and brain metabolism in 21 non-diabetics aged 55 years old or older. Empagliflozin lowered circulating insulin and elevated ß-hydroxybutyrate over 34-h periods, both following its first administration and after 14 days of daily administration, with minor alterations in glucose homeostasis. Levels of phosphorylated insulin-like growth factor-1 receptor (pIGF-1R), phosphorylated insulin receptor (pIR), phosphorylated-in-tyrosine insulin receptor substrate-1 (pY-IRS-1), and phosphorylated protein kinase B or AKT (pAKT) were increased in extracellular vesicles enriched for neuronal origin (NEVs) following the first empagliflozin administration, but not after 14 days. Our finding of IGF-1R upregulation in NEVs is promising because several post-mortem and epidemiological studies support the idea that upregulation of IGF signaling may protect against Alzheimer's disease (AD). Moreover, our finding showing activation of insulin signaling and, in particular, the canonical pathway (pIR, pY-IRS-1, pAKT) in NEVs is important because such changes have been repeatedly associated with neuronal survival. Using brain magnetic resonance spectroscopy (MRS), we detected decreased concentrations of the excitatory neurotransmitter glutamate and its precursor glutamine after empagliflozin administration. This finding is also encouraging since glutamatergic excitotoxicity has long been implicated in AD pathology. Overall, our findings may motivate the repurposing of SGLT2is for use in AD and other, related diseases that are characterized by downregulation of IGF-1/insulin signaling in neurons and excitotoxicity.
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Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Cetosis , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Femenino , Humanos , Persona de Mediana Edad , Enfermedad de Alzheimer/metabolismo , Glucemia/metabolismo , Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Ácido Glutámico/metabolismo , Insulina/metabolismo , Insulina Regular Humana/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Cetosis/metabolismo , Neuronas/metabolismo , Neurotransmisores/metabolismo , Factor de Crecimiento Placentario/metabolismo , Factor de Crecimiento Placentario/farmacología , Receptor de Insulina/metabolismo , Transducción de Señal , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacologíaRESUMEN
OBJECTIVE: To investigate the effects of monoclonal antibodies against Aß on cognition, function, amyloid PET and other biomarkers, as well as risk for amyloid-related imaging abnormalities (ARIA) and other adverse events, in Alzheimer's disease (AD). METHODS: Pubmed, Web of Science, ClinicalTrials.gov and gray literature were searched for phase III RCTs and random-effects meta-analyses were performed. RESULTS: Seventeen studies (12,585 patients) were included. Antibodies statistically improved the cognitive outcomes ADAS-Cog {SMD = -0.06 [95 % CI (-0.10; -0.02), I2 = 0%]} and MMSE {SMD = 0.05 [95 % CI (0.01; 0.09), I2 = 0%]} by small effect sizes, but did not improve the cognitive/functional measure CDR-SOB {SMD = -0.03 [95 % CI (-0.07; 0.01), I2 = 18 %]}. Moreover, antibodies decreased amyloid PET SUVR {SMD = -1.02 [95 % CI (-1.70; -0.34), I2 = 95 %]} and CSF p181-tau {SMD = -0.87 [95 % CI (-1.32; -0.43), I2 = 89 %]} by large effect sizes. They also increased risk for ARIA {RR = 4.30 [95 % CI (2.39; 7.77), I2 = 86 %]} by a large effect size. Antibody effects on reducing amyloid PET SUVR were correlated with their effects on improving ADAS-Cog (r = +0.68, p = 0.02). In subgroup analyses by individual drug, Aducanumab improved ADAS-Cog, CDR-SOB, ADCS-ADL by small effect sizes and decreased amyloid PET SUVR and CSF p181-tau by large effect sizes. Solanezumab improved ADAS-Cog and MMSE by small effect sizes, and increased (improved) CSF Aß1-40 levels by a moderate effect size. Bapineuzumab, Gantenerumab and Crenezumab did not improve any clinical outcomes. Bapineuzumab and Gantenerumab decreased CSF p181-tau by a small and large effect size, respectively. All drugs except Solanezumab increased ARIA risk. CONCLUSIONS: In this meta-analysis of phase III trials in AD, we found that monoclonal antibodies against Aß induced clinical improvements of small effect sizes, biomarker improvements of large effect sizes, and increases in risk for the hallmark adverse event, ARIA, by a large effect size, when all drugs were pooled together. Among individual drugs, Aducanumab produced the most favorable effects followed by Solanezumab. These findings provide moderate support for the continuous development of anti-Aß monoclonal antibodies as a treatment for AD.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides , Proteínas Amiloidogénicas , Anticuerpos Monoclonales/efectos adversos , Biomarcadores , Ensayos Clínicos Fase III como Asunto , Cognición , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
To meet its high energy demands, the brain mostly utilizes glucose. However, the brain has evolved to exploit additional fuels, such as ketones, especially during prolonged fasting. With aging and neurodegenerative diseases (NDDs), the brain becomes inefficient at utilizing glucose due to changes in glia and neurons that involve glucose transport, glycolytic and Krebs cycle enzyme activities, and insulin signaling. Positron emission tomography and magnetic resonance spectroscopy studies have identified glucose metabolism abnormalities in aging, Alzheimer's disease (AD) and other NDDs in vivo. Despite glucose hypometabolism, brain cells can utilize ketones efficiently, thereby providing a rationale for the development of therapeutic ketogenic interventions in AD and other NDDs. This review compares available ketogenic interventions and discusses the potential of the potent oral Ketone Ester for future therapeutic use in AD and other NDDs characterized by inefficient glucose utilization.
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Envejecimiento/metabolismo , Encéfalo/metabolismo , Dieta Cetogénica , Glucosa/metabolismo , Insulina/metabolismo , Cuerpos Cetónicos/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/dietoterapia , Enfermedad de Alzheimer/metabolismo , Animales , Humanos , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/dietoterapiaRESUMEN
INTRODUCTION/AIM: The brain in Alzheimer's disease shows glucose hypometabolism but may utilize ketones for energy production. Ketone levels can potentially be boosted through oral intake of Medium Chain Triglycerides (MCTs). The aim of this meta-analysis is to investigate the effect of MCTs on peripheral ketone levels and cognitive performance in patients with mild cognitive impairment and Alzheimer's disease. METHODS: Medline, Scopus and Web of Science were searched for literature up to March 1, 2019. Meta-analyses were performed by implementing continuous random-effects models and outcomes were reported as weighted Mean Differences (MDs) or Standardized Mean Differences (SMDs). RESULTS: Twelve records (422 participants) were included. Meta-analysis of RCTs showed that, compared with placebo, MCTs elevated beta-hydroxybutyrate [MD = 0.355; 95 % CI (0.286, 0.424), I2 = 0 %], showed a trend towards cognitive improvement on ADAS-Cog [MD = -0.539; 95% CI (-1.239, -0.161), I2 = 0 %], and significantly improved cognition on a combined measure (ADAS-Cog with MMSE) [SMD = -0.289; 95 % CI (-0.551, -0.027), I2 = 0 %]. CONCLUSIONS: In this meta-analysis, we demonstrated that MCTs can induce mild ketosis and may improve cognition in patients with mild cognitive impairment and Alzheimer's disease. However, risk of bias of existing studies necessitates future trials.
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Enfermedad de Alzheimer , Trastornos del Conocimiento , Cetosis , Triglicéridos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/tratamiento farmacológico , Cognición , Trastornos del Conocimiento/tratamiento farmacológico , Humanos , Triglicéridos/farmacologíaRESUMEN
Continuously rising trends in obesity-related malignancies render this disease spectrum a public health priority. Worldwide, the burden of cancer attributable to obesity, expressed as population attributable fraction, is 11.9% in men and 13.1% in women. There is convincing evidence that excess body weight is associated with an increased risk for cancer of at least 13 anatomic sites, including endometrial, esophageal, renal and pancreatic adenocarcinomas; hepatocellular carcinoma; gastric cardia cancer; meningioma; multiple myeloma; colorectal, postmenopausal breast, ovarian, gallbladder and thyroid cancers. We first synopsize current epidemiologic evidence; the obesity paradox in cancer risk and mortality; the role of weight gain and weight loss in the modulation of cancer risk; reliable somatometric indicators for obesity and cancer research; and gender differences in obesity related cancers. We critically summarize emerging biological mechanisms linking obesity to cancer encompassing insulin resistance and abnormalities of the IGF-I system and signaling; sex hormones biosynthesis and pathway; subclinical chronic low-grade inflammation and oxidative stress; alterations in adipokine pathophysiology; factors deriving from ectopic fat deposition; microenvironment and cellular perturbations including vascular perturbations, epithelial-mesenchymal transition, endoplasmic reticulum stress and migrating adipose progenitor cells; disruption of circadian rhythms; dietary nutrients; factors with potential significance such as the altered intestinal microbiome; and mechanic factors in obesity and cancer. Future perspectives regarding prevention, diagnosis and therapeutics are discussed. The aim of this review is to investigate how the interplay of these main potential mechanisms and risk factors, exerts their effects on target tissues provoking them to acquire a cancerous phenotype.
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Neoplasias/complicaciones , Neoplasias/epidemiología , Obesidad/complicaciones , Obesidad/epidemiología , Femenino , Humanos , Masculino , Riesgo , Caracteres SexualesRESUMEN
BACKGROUND AND AIMS: Creatine is a supplement used by sportsmen to increase athletic performance by improving energy supply to muscle tissues. It is also an essential brain compound and some hypothesize that it aids cognition by improving energy supply and neuroprotection. The aim of this systematic review is to investigate the effects of oral creatine administration on cognitive function in healthy individuals. METHODS: A search of multiple electronic databases was performed for the identification of randomized clinical trials (RCTs) examining the cognitive effects of oral creatine supplementation in healthy individuals. RESULTS: Six studies (281 individuals) met our inclusion criteria. Generally, there was evidence that short term memory and intelligence/reasoning may be improved by creatine administration. Regarding other cognitive domains, such as long-term memory, spatial memory, memory scanning, attention, executive function, response inhibition, word fluency, reaction time and mental fatigue, the results were conflicting. Performance on cognitive tasks stayed unchanged in young individuals. Vegetarians responded better than meat-eaters in memory tasks but for other cognitive domains no differences were observed. CONCLUSIONS: Oral creatine administration may improve short-term memory and intelligence/reasoning of healthy individuals but its effect on other cognitive domains remains unclear. Findings suggest potential benefit for aging and stressed individuals. Since creatine is safe, future studies should include larger sample sizes. It is imperative that creatine should be tested on patients with dementias or cognitive impairment.
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Cognición , Creatina/administración & dosificación , Suplementos Dietéticos , Voluntarios Sanos , Humanos , Inteligencia , Memoria a Corto Plazo , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
PURPOSE OF REVIEW: In this review, we investigate the role of classic and novel adipocytokines in cancer pathogenesis synopsizing the mechanisms underlying the association between adipocytokines and malignancy. Special emphasis is given on novel adipocytokines as new evidence is emerging regarding their entanglement in neoplastic development. RECENT FINDINGS: Recent data have emphasized the role of the triad of overweight/obesity, insulin resistance and adipocytokines in cancer. In the setting of obesity, classic and novel adipocytokines present independent and joint effects on activation of major intracellular signaling pathways implicated in cell proliferation, expansion, survival, adhesion, invasion, and metastasis. Until now, more than 15 adipocytokines have been associated with cancer, and this list continues to expand. While the plethora of circulating pro-inflammatory adipocytokines, such as leptin, resistin, extracellular nicotinamide phosphoribosyl transferase, and chemerin are elevated in malignancies, some adipocytokines such as adiponectin and omentin-1 are generally decreased in cancers and are considered protective against carcinogenesis. Elucidating the intertwining of inflammation, cellular bioenergetics, and adiposopathy is significant for the development of preventive, diagnostic, and therapeutic strategies against cancer. Novel more effective and safe adipocytokine-centered therapeutic interventions may pave the way for targeted oncotherapy.