RESUMEN
BACKGROUND: Gait-related changes in older adulthood may be related to changes in cognition (e.g., executive functioning), and recent work suggests that different self-reported measures of sleep may be tied to contrasting aspects of executive functioning. However, the relationship between these self-reported sleep measures and gait domains has not been explored. Such an investigation would be useful in helping to determine which older adults might exhibit changes in gait as well as experience other gait-associated changes (e.g., increased fall risk). OBJECTIVE: To examine associations between different aspects of self-reported sleep and gait domains in a sample of cognitively healthy older adults. METHOD: A total of 423 older adults (mean age 69.9 years, range 50-92) completed self-report measures of sleep quality, daytime sleepiness, and sleep-related distress. The participants also completed an objective, electronic measure of both single-task and dual-task gait (i.e., GAITRite). Principal component analyses were used to elucidate the solution for each gait condition, and multiple linear regression was used to examine the contributions of sleep measures to variability in gait performance. RESULTS: A 5-component solution of the single-task condition and a 4-component solution of the dual-task condition were identified. Multiple linear regressions revealed that a poorer sleep quality was associated with greater single-task and dual-task asymmetry. Greater daytime sleepiness was associated with increased dual-task gait variability and postural control. After controlling for the effects of other facets of sleep, sleep-related distress was not associated with any gait domain. CONCLUSIONS: Among cognitively healthy older adults,sleep quality and daytime sleepiness, but not sleep-related distress, are associated with aspects of gait. Patients who report these symptoms should be assessed and monitored for possible changes in gait.
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Cognición/fisiología , Marcha/fisiología , Sueño/fisiología , Anciano , Anciano de 80 o más Años , Función Ejecutiva , Femenino , Humanos , Louisiana , Masculino , Persona de Mediana Edad , Autoinforme , Trastornos del Inicio y del Mantenimiento del Sueño/complicacionesRESUMEN
Recently, we showed that rivastigmine decreased amyloid-ß (Aß) brain load in aged rats by enhancing its clearance across the blood-brain barrier (BBB) via upregulation of P-glycoprotein (P-gp) and low-density lipoprotein receptor-related protein 1 (LRP1). Here, we extend our previous work to clarify P-gp role in mediating rivastigmine effect on Aß brain levels and neuroprotection in a mouse model of Alzheimer's disease (AD) that expresses different levels of P-gp. APPSWE mice were bred with mdr1a/b knockout mice to produce littermates that were divided into three groups; APP(+)/mdr1(+/+), APP(+)/mdr1(+/-) and APP(+)/mdr1(-/-). Animals received rivastigmine treatment (0.3mg/kg/day) or vehicle for 8weeks using Alzet osmotic mini-pumps. ELISA analysis of brain homogenates for Aß showed rivastigmine treatment to significantly decrease Aß brain load in APP(+)/mdr1(+/+) by 25% and in APP(+)/mdr1(+/-) mice by 21% compared to their vehicle treated littermates, but not in APP(+)/mdr1(-/-) mice. In addition, rivastigmine reduced GFAP immunostaining of astrocytes by 50% and IL-1ß brain level by 43% in APP(+)/mdr1(+/+) mice, however its effect was less pronounced in P-gp knockout mice. Moreover, rivastigmine demonstrated a P-gp expression dependent neuroprotective effect that was highest in APP(+)/mdr1(+/+)>APP(+)/mdr1(+/-)>APP(+)/mdr1(-/-) as determined by expression of synaptic markers PSD-95 and SNAP-25 using Western blot analysis. Collectively, our results suggest that P-gp plays important role in mediating rivastigmine non-cholinergic beneficial effects, including Aß brain load reduction, neuroprotective and anti-inflammatory effects in the AD mouse models.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Rivastigmina/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Animales , Modelos Animales de Enfermedad , Homólogo 4 de la Proteína Discs Large/genética , Homólogo 4 de la Proteína Discs Large/metabolismo , Humanos , Ratones , Ratones Transgénicos , Ratas , Rivastigmina/farmacocinética , Proteína 25 Asociada a Sinaptosomas/genética , Proteína 25 Asociada a Sinaptosomas/metabolismoRESUMEN
Recent clinical and laboratory evidences suggest that high fat diet (HFD) induced obesity and its associated metabolic syndrome conditions promotes neuropathology in aging and age-related neurological disorders. However, the effects of high fat diet on brain pathology are poorly understood, and the effective strategies to overcome these effects remain elusive. In the current study, we examined the effects of HFD on brain pathology and further evaluated whether donepezil, an AChE inhibitor with neuroprotective functions, could suppress the ongoing HFD induced pathological changes in the brain. Our data demonstrates that HFD induced obesity results in increased neuroinflammation and increased AChE activity in the brain when compared with the mice fed on low fat diet (LFD). HFD administration to mice activated mTOR pathway resulting in increased phosphorylation of mTOR(ser2448), AKT(thr308) and S6K proteins involved in the signaling. Interestingly, donepezil administration with HFD suppressed HFD induced increases in AChE activity, and partially reversed HFD effects on microglial reactivity and the levels of mTOR signaling proteins in the brain when compared to the mice on LFD alone. However, gross levels of synaptic proteins were not altered in the brain tissues of mice fed either diet with or without donepezil. In conclusion, these results present a new insight into the detrimental effects of HFD on brain via microglial activation and involvement of mTOR pathway, and further demonstrates the possible therapeutic role for donepezil in ameliorating the early effects of HFD that could help preserve the brain function in metabolic syndrome conditions.
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Encéfalo/efectos de los fármacos , Inhibidores de la Colinesterasa/uso terapéutico , Dieta Alta en Grasa/efectos adversos , Donepezilo/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/etiología , Serina-Treonina Quinasas TOR/inmunología , Animales , Encéfalo/inmunología , Encéfalo/patología , Inhibidores de la Colinesterasa/farmacología , Donepezilo/farmacología , Inflamación/inmunología , Inflamación/patología , Masculino , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Obesidad/tratamiento farmacológico , Obesidad/etiología , Obesidad/inmunología , Transducción de Señal/efectos de los fármacos , Sinapsis/efectos de los fármacos , Sinapsis/inmunología , Sinapsis/patologíaRESUMEN
HIV protease inhibitors are key components of HIV antiretroviral therapies, which are fundamental in the treatment of HIV infection. However, the protease inhibitors are well-known to induce metabolic dysfunction which can in turn escalate the complications of HIV, including HIV associated neurocognitive disorders. As experimental and epidemiological data support a therapeutic role for adiponectin in both metabolic and neurologic homeostasis, this study was designed to determine if increased adiponectin could prevent the detrimental effects of protease inhibitors in mice. Adult male wild type (WT) and adiponectin-overexpressing (ADTg) mice were thus subjected to a 4-week regimen of lopinavir/ritonavir, followed by comprehensive metabolic, neurobehavioral, and neurochemical analyses. Data show that lopinavir/ritonavir-induced lipodystrophy, hypoadiponectinemia, hyperglycemia, hyperinsulinemia, and hypertriglyceridemia were attenuated in ADTg mice. Furthermore, cognitive function and blood-brain barrier integrity were preserved, while loss of cerebrovascular markers and white matter injury were prevented in ADTg mice. Finally, lopinavir/ritonavir caused significant increases in expression of markers of brain inflammation and decreases in synaptic markers in WT, but not in ADTg mice. Collectively, these data reinforce the pathophysiologic link from metabolic dysfunction to loss of cerebrovascular and cognitive homeostasis; and suggest that preservation and/or replacement of adiponectin could prevent these key aspects of HIV protease inhibitor-induced toxicity in clinical settings.
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Adiponectina/metabolismo , Lesiones Encefálicas/inducido químicamente , Encéfalo/irrigación sanguínea , Inhibidores de la Proteasa del VIH/efectos adversos , Lopinavir/efectos adversos , Ritonavir/efectos adversos , Adiponectina/genética , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Cognición/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Homeostasis/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Regulación hacia ArribaRESUMEN
Several integrated proteolytic systems contribute to the maintenance of cellular homeostasis through the continuous removal of misfolded, aggregated or oxidized proteins and damaged organelles. Among these systems, the proteasome and autophagy play the major role in protein quality control, which is a fundamental issue in non-proliferative cells such as neurons. Disturbances in the functionality of these two pathways are frequently observed in neurodegenerative diseases, like Alzheimer's disease, and reflect the accumulation of protease-resistant, deleterious protein aggregates. In this review, we explored the sophisticated crosstalk between the ubiquitin-proteasome system and autophagy in the removal of the harmful structures that characterize Alzheimer's disease neurons. We also dissected the role of the numerous shuttle factors and chaperones that, directly or indirectly interacting with ubiquitin and LC3, are used for cargo selection and delivery to one pathway or the other.
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Enfermedad de Alzheimer/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismo , Enfermedad de Alzheimer/metabolismo , Autofagia , Humanos , Proteínas Asociadas a Microtúbulos/metabolismo , Chaperonas Moleculares/metabolismo , Neuronas/metabolismo , ProteolisisRESUMEN
Senile amyloid plaques are one of the diagnostic hallmarks of Alzheimer's disease (AD). However, the severity of clinical symptoms of AD is weakly correlated with the plaque load. AD symptoms severity is reported to be more strongly correlated with the level of soluble amyloid-ß (Aß) assemblies. Formation of soluble Aß assemblies is stimulated by monomeric Aß accumulation in the brain, which has been related to its faulty cerebral clearance. Studies tend to focus on the neurotoxicity of specific Aß species. There are relatively few studies investigating toxic effects of Aß on the endothelial cells of the blood-brain barrier (BBB). We hypothesized that a soluble Aß pool more closely resembling the in vivo situation composed of a mixture of Aß40 monomer and Aß42 oligomer would exert higher toxicity against hCMEC/D3 cells as an in vitro BBB model than either component alone. We observed that, in addition to a disruptive effect on the endothelial cells integrity due to enhancement of the paracellular permeability of the hCMEC/D3 monolayer, the Aß mixture significantly decreased monomeric Aß transport across the cell culture model. Consistent with its effect on Aß transport, Aß mixture treatment for 24h resulted in LRP1 down-regulation and RAGE up-regulation in hCMEC/D3 cells. The individual Aß species separately failed to alter Aß clearance or the cell-based BBB model integrity. Our study offers, for the first time, evidence that a mixture of soluble Aß species, at nanomolar concentrations, disrupts endothelial cells integrity and its own transport across an in vitro model of the BBB.
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Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/patología , Endotelio Vascular/patología , Microvasos/patología , Placa Amiloide/patología , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Transporte Biológico , Barrera Hematoencefálica/metabolismo , Western Blotting , Encéfalo/metabolismo , Células Cultivadas , Dimerización , Endotelio Vascular/metabolismo , Humanos , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Microvasos/metabolismo , Placa Amiloide/metabolismo , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/metabolismoRESUMEN
Cells rely on complementary proteolytic pathways including the ubiquitin-proteasome system and autophagy to maintain proper protein degradation. There is known to be considerable interplay between them, whereby the loss of one clearance system results in compensatory changes in other proteolytic pathways of the cell. Disturbances in proteolysis are known to occur in Alzheimer's disease, and potentially contribute to neurophysiological and neurodegenerative processes. Currently, few data are available on how the presence of wild type and mutant amyloid precursor protein (APPwt and APPmut) potentially alters the reciprocal interplay between the different intracellular proteolytic pathways. This study used human SH-SY5Y neuronal cell lines, and SH-SY5Y transfected with either APPwt or APPmut (valine-to-glycine substitution at position 717), in order to explore if the presence of APPwt or APPmut altered the downstream effects of pharmacological proteasome or autophagy inhibition. The occurrence of APPwt or APPmut was observed to disturb proteasome or autophagy activities upon treatment with proteasome inhibitors or authophagy inhibitors. Interestingly, APPwt and APPmut expression was observed to significantly and robustly enhance the induction in cathepsin B following the administration of an established proteasome inhibitor. The presence of APPwt and APPmut also significantly reduced the elevation in ubiquitinated proteins following proteasome inhibitor treatments. Our data strongly suggest that APP is able to affect the downstream effects of protease inhibition in neural cells including enhancement of cathepsin B activity, with these changes in cathepsin B significantly and inversely related to the levels of ubiquitinated protein.
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Precursor de Proteína beta-Amiloide/metabolismo , Autofagia/fisiología , Proteínas Mutantes/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Adenina/análogos & derivados , Adenina/farmacología , Sustitución de Aminoácidos , Precursor de Proteína beta-Amiloide/genética , Autofagia/efectos de los fármacos , Western Blotting , Catepsina B/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Inhibidores de Cisteína Proteinasa/farmacología , Humanos , Inmunohistoquímica , Leupeptinas/farmacología , Proteínas Mutantes/genética , Mutación , Proteolisis/efectos de los fármacosRESUMEN
Cerebral amyloid angiopathy (CAA) occurs in nearly every individual with Alzheimer's disease (AD) and Down's syndrome, and is the second largest cause of intracerebral hemorrhage. Mouse models of CAA have demonstrated evidence for increased gliosis contributing to CAA pathology. Nearly two thirds of Americans are overweight or obese, with little known about the effects of obesity on the brain, although increasingly the vasculature appears to be a principle target of obesity effects on the brain. In the current study we describe for the first time whether diet induced obesity (DIO) modulates glial reactivity, amyloid levels, and inflammatory signaling in a mouse model of CAA. In these studies we identify surprisingly that DIO does not significantly increase Aß levels, astrocyte (GFAP) or microglial (IBA-1) gliosis in the CAA mice. However, within the hippocampal gyri a localized increase in reactive microglia were increased in the CA1 and stratum oriens relative to CAA mice on a control diet. DIO was observed to selectively increase IL-6 in CAA mice, with IL-1ß and TNF-α not increased in CAA mice in response to DIO. Taken together, these data show that prolonged DIO has only modest effects towards Aß in a mouse model of CAA, but appears to elevate some localized microglial reactivity within the hippocampal gyri and selective markers of inflammatory signaling. These data are consistent with the majority of the existing literature in other models of Aß pathology, which surprisingly show a mixed profile of DIO effects towards pathological processes in mouse models of neurodegenerative disease. The importance for considering the potential impact of ceiling effects in pathology within mouse models of Aß pathogenesis, and the current experimental limitations for DIO in mice to fully replicate metabolic dysfunction present in human obesity, are discussed. This article is part of a Special Issue entitled: Animal Models of Disease.
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Enfermedad de Alzheimer/complicaciones , Encéfalo/patología , Angiopatía Amiloide Cerebral/etiología , Dieta/efectos adversos , Modelos Animales de Enfermedad , Gliosis/etiología , Obesidad/etiología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Western Blotting , Encéfalo/metabolismo , Angiopatía Amiloide Cerebral/patología , Femenino , Gliosis/patología , Humanos , Técnicas para Inmunoenzimas , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/patología , Obesidad/patología , Placa Amiloide/patología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, affecting an estimated 5.3million people in the United States. While many factors likely contribute to AD progression, it is widely accepted that AD is driven by the accumulation of ß-amyloid (Aß), a small, fibrillogenic peptide generated by the sequential proteolysis of the amyloid precursor protein by the ß- and γ-secretases. Though the underlying causes of Aß accumulation in sporadic AD are myriad, it is clear that lifestyle and overall health play a significant role. The adipocyte-derived hormone leptin has varied systemic affects, including neuropeptide release and neuroprotection. A recent study by Lieb et al. (2009) showed that individuals with low plasma leptin levels are at greater risk of developing AD, through unknown mechanisms. In this report, we show that plasma leptin is a strong negative predictor of Aß levels in the mouse brain, supporting a protective role for the hormone in AD onset. We also show that the inhibition of Aß accumulation is due to the downregulation of transcription of the γ-secretase components. On the other hand, ß-secretase expression is either unchanged (BACE1) or increased (BACE2). Finally, we show that only presenilin 1 (PS1) is negatively correlated with plasma leptin at the protein level (p<0.0001). These data are intriguing and may highlight a role for leptin in regulating the onset of amyloid pathology and AD.
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Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Leptina/sangre , Secretasas de la Proteína Precursora del Amiloide/genética , Péptidos beta-Amiloides/biosíntesis , Animales , Encéfalo/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Expresión Génica/efectos de los fármacos , Humanos , Immunoblotting , Leptina/farmacología , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Presenilina-1/genética , Presenilina-1/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
While numerous lines of evidence point to increased levels of oxidative stress playing a causal role in a number of neurodegenerative conditions, our current understanding of the specific role of oxidative stress in the genesis and/or propagation of neurodegenerative diseases remains poorly defined. Even more challenging to the "oxidative stress theory of neurodegeneration" is the fact that many antioxidant-based clinical trials and therapeutic interventions have been largely disappointing in their therapeutic benefit. Together, these factors have led researchers to begin to focus on understanding the contribution of highly localized structures, and defined anatomical features, within the brain as the sites responsible for oxidative stress-induced neurodegeneration. This review focuses on the potential for oxidative stress within the cerebrovascular architecture serving as a modulator of neurodegeneration in a variety of pathological settings. In particular, this review highlights important implications for vascular-derived oxidative stress in the initiating and promoting pathophysiology in the brain, identifying new roles for cerebrovascular oxidative stress in a variety of brain disorders. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.
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Antioxidantes/uso terapéutico , Barrera Hematoencefálica , Encéfalo/irrigación sanguínea , Endotelio Vascular/metabolismo , Estrés Oxidativo , Endotelio Vascular/citología , HumanosRESUMEN
The fruit fly Drosophila melanogaster is increasingly utilized as an alternative to costly rodent models to study human diseases. Fly models exist for a wide variety of human conditions, such as Alzheimer's and Parkinson's Disease, or cardiac function. Advantages of the fly system are its rapid generation time and its low cost. However, the greatest strength of the fly system are the powerful genetic tools that allow for rapid dissection of molecular disease mechanisms. Here, we describe the diet-dependent development of metabolic phenotypes in adult fruit flies. Depending on the specific type of nutrient, as well as its relative quantity in the diet, flies show weight gain and changes in the levels of storage macromolecules. Furthermore, the activity of insulin-signaling in the major metabolic organ of the fly, the fat body, decreases upon overfeeding. This decrease in insulin-signaling activity in overfed flies is moreover observed when flies are challenged with an acute food stimulus, suggesting that overfeeding leads to insulin resistance. Similar changes were observed in aging flies, with the development of the insulin resistance-like phenotype beginning at early middle ages. Taken together, these data demonstrate that imbalanced diet disrupts metabolic homeostasis in adult D. melanogaster and promotes insulin-resistant phenotypes. Therefore, the fly system may be a useful alternative tool in the investigation of molecular mechanisms of insulin resistance and the development of pharmacologic treatment options.
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Drosophila melanogaster/metabolismo , Resistencia a la Insulina/fisiología , Factores de Edad , Animales , Grasas de la Dieta/metabolismo , Proteínas en la Dieta/metabolismo , Modelos Animales de Enfermedad , Insulina/metabolismo , Transducción de Señal , Sacarosa/metabolismoRESUMEN
The consumption of high-fat/calorie diets in modern societies is likely a major contributor to the obesity epidemic, which can increase the prevalence of cancer, cardiovascular disease, and neurological impairment. Obesity may precipitate decline via inflammatory and oxidative signaling, and one factor linking inflammation to oxidative stress is the proinflammatory, pro-oxidant enzyme NADPH oxidase. To reveal the role of NADPH oxidase in the metabolic and neurological consequences of obesity, the effects of high-fat diet were compared in wild-type C57Bl/6 (WT) mice and in mice deficient in the NAPDH oxidase subunit NOX2 (NOX2KO). While diet-induced weight gains in WT and NOX2KO mice were similar, NOX2KO mice had smaller visceral adipose deposits, attenuated visceral adipocyte hypertrophy, and diminished visceral adipose macrophage infiltration. Moreover, the detrimental effects of HFD on markers of adipocyte function and injury were attenuated in NOX2KO mice; NOX2KO mice had improved glucose regulation, and evaluation of NOX2 expression identified macrophages as the primary population of NOX2-positive cells in visceral adipose. Finally, brain injury was assessed using markers of cerebrovascular integrity, synaptic density, and reactive gliosis, and data show that high-fat diet disrupted marker expression in WT but not NOX2KO mice. Collectively, these data indicate that NOX2 is a significant contributor to the pathogenic effects of high-fat diet and reinforce a key role for visceral adipose inflammation in metabolic and neurological decline. Development of NOX-based therapies could accordingly preserve metabolic and neurological function in the context of metabolic syndrome.
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Adiposidad , Encéfalo/metabolismo , Dieta Alta en Grasa/efectos adversos , Glicoproteínas de Membrana/deficiencia , NADPH Oxidasas/deficiencia , Neuronas/metabolismo , Obesidad/metabolismo , Subunidades de Proteína/deficiencia , Animales , Biomarcadores/metabolismo , Encéfalo/inmunología , Encéfalo/patología , Hipertrofia , Grasa Intraabdominal/inmunología , Grasa Intraabdominal/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Síndrome Metabólico/etiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , NADPH Oxidasa 2 , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/inmunología , Neuronas/patología , Obesidad/inmunología , Obesidad/patología , Obesidad/fisiopatología , Estrés Oxidativo , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Aumento de PesoRESUMEN
OBJECTIVE: Deposition of the amyloid-ß (Aß) peptide in neuritic plaques is a requirement for the diagnosis of Alzheimer disease (AD). Although the continued development of in vivo imaging agents such as Pittsburgh compound B (PiB) is promising, the diagnosis of AD is still challenging. This can be partially attributed to our lack of a detailed understanding of the interrelationship between the various pools and species of Aß and other common indices of AD pathology. We hypothesized that recent advances in our ability to accurately measure Aß postmortem (for example, using PiB), could form the basis of a simple means to deliver an accurate AD diagnosis. METHODS: We conducted a comprehensive analysis of the amount of Aß40 and Aß42 in increasingly insoluble fractions, oligomeric Aß, and fibrillar Aß (as defined by PiB binding), as well as plaques (diffuse and neuritic), and neurofibrillary tangles in autopsy specimens from age-matched, cognitively normal controls (n = 23) and AD (n = 22) cases, across multiple brain regions. RESULTS: Both PiB binding and the amount of sodium dodecyl sulfate (SDS)-soluble Aß were able to predict disease status; however, SDS-soluble Aß was a better measure. Oligomeric Aß was not a predictor of disease status. PiB binding was strongly related to plaque count, although diffuse plaques were a stronger correlate than neuritic plaques. INTERPRETATION: Although postmortem PiB binding was somewhat useful in distinguishing AD from control cases, SDS-soluble Aß measured by standard immunoassay was substantially better. These findings have important implications for the development of imaging-based biomarkers of AD.
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Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Compuestos de Anilina , Radiofármacos , Tiazoles , Anciano de 80 o más Años , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/metabolismo , Autopsia , Biomarcadores , Encéfalo/patología , Química Encefálica , Femenino , Humanos , Masculino , Ovillos Neurofibrilares/genética , Ovillos Neurofibrilares/patología , Pruebas Neuropsicológicas , Placa Amiloide/metabolismo , Valor Predictivo de las Pruebas , Cintigrafía , Dodecil Sulfato de Sodio/química , Solubilidad , Tensoactivos/químicaRESUMEN
The purpose of this study was to compare the steps/d derived from the ActiGraph GT3X+ using the manufacturer's default filter (DF) and low-frequency-extension filter (LFX) with those from the NL-1000 pedometer in an older adult sample. Fifteen older adults (61-82 yr) wore a GT3X+ (24 hr/day) and an NL-1000 (waking hours) for 7 d. Day was the unit of analysis (n = 86 valid days) comparing (a) GT3X+ DF and NL-1000 steps/d and (b) GT3X+ LFX and NL-1000 steps/d. DF was highly correlated with NL-1000 (r = .80), but there was a significant mean difference (-769 steps/d). LFX and NL-1000 were highly correlated (r = .90), but there also was a significant mean difference (8,140 steps/d). Percent difference and absolute percent difference between DF and NL-1000 were -7.4% and 16.0%, respectively, and for LFX and NL-1000 both were 121.9%. Regardless of filter used, GT3X+ did not provide comparable pedometer estimates of steps/d in this older adult sample.
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Monitoreo Ambulatorio/instrumentación , Caminata/fisiología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Soybean products have nutrients, dietary fiber, and phytoalexins beneficial for cardiovascular and overall health. Despite their high consumption in Asian populations, their safety in Western diets is debated. We conducted a dose-escalating clinical trial of the safety and tolerability of soybean products in eight older adults (70-85 years) with obesity. Whole green soybean pods grown under controlled conditions were processed to flour (WGS) at the United States Department of Agriculture using common cooking techniques such as slicing and heat treatment. WGS incorporated into food products was consumed at 10 g, 20 g, and 30 g/day for one week at each dose. The gastrointestinal outcomes, clinical biomarkers, and adverse events were evaluated. We explored the stimulation of phytoalexin (glyceollin) production in live viable soybean seeds (LSS-G). We compared the compositions of WGS and LSS-G with commercial soybean flour and its fermented and enzymatically hydrolyzed forms. We found that although 30 g WSG was well-tolerated, and it made participants feel full. Our processing produced glyceollins (267 µg/g) in LSS-G. Processing soybean flour decreased the iron content, but reduced the oligosaccharides, which could attenuate flatulence. Providing soybean flour at <30 g/day may be prudent for overall health and to prevent the exclusion of other food groups and nutrients in older adults with obesity.
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Glycine max , Obesidad , Anciano , Humanos , Fibras de la Dieta , Oligosacáridos/efectos adversos , SemillasRESUMEN
INTRODUCTION: The risk reduction for Alzheimer's disease (rrAD) trial was a multisite clinical trial to assess exercise and intensive vascular pharmacological treatment on cognitive function in community-dwelling older adults at increased risk for Alzheimer's disease. METHODS: Eligibility, consent, and randomization rates across different referral sources were compared. Informal interviews conducted with each site's project team were conducted upon study completion. RESULTS: Initially, 3290 individuals were screened, of whom 28% were eligible to consent, 805 consented to participate (87.2% of those eligible), and 513 (36.3% of those consented) were randomized. Emails sent from study site listservs/databases yielded the highest amount (20.9%) of screened individuals. Professional referrals from physicians yielded the greatest percentage of consented individuals (57.1%). Referrals from non-professional contacts (ie, friends, family; 75%) and mail/phone contact from a site (73.8%) had the highest yield of randomization. DISCUSSION: Professional referrals or email from listservs/registries were most effective for enrolling participants. The greatest yield of eligible/randomized participants came from non-professional and mail/phone contacts. Future trials should consider special efforts targeting these recruitment approaches. Highlights: Clinical trial recruitment is commonly cited as a significant barrier to advancing our understanding of cognitive health interventions.The most cited referral source was email, followed by interviews/editorials on the radio, television, local newspapers, newsletters, or magazine articles.The referral method that brought in the largest number of contacts was email but did not result in the greatest yield of consents or eligible participants.The sources that yielded the greatest likelihood of consent were professional referrals (ie, physician), social media, and mail/phone contact from study site.The greatest yield of eligible/randomized participants came from non-professional contacts and mail/phone contact from a site.Findings suggest that sites may need to focus on more selective referral sources, such as using contact mailing and phone lists, rather than more widely viewed recruitment sources, such as social media or TV/radio advertisements.
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This study describes the effects of long-chain fatty acids on inflammatory signaling in cultured astrocytes. Data show that the saturated fatty acid palmitic acid, as well as lauric acid and stearic acid, trigger the release of TNFα and IL-6 from astrocytes. Unsaturated fatty acids were unable to induce cytokine release from cultured astrocytes. Furthermore, the effects of palmitic acid on cytokine release require Toll-like receptor 4 rather than CD36 or Toll-like receptor 2, and do not depend on palmitic acid metabolism to palmitoyl-CoA. Inhibitor studies revealed that pharmacologic inhibition of p38 or p42/44 MAPK pathways prevents the pro-inflammatory effects of palmitic acid, whereas JNK and PI3K inhibition does not affect cytokine release. Depletion of microglia from primary astrocyte cultures using the lysosomotropic agent l-leucine methyl ester revealed that the ability of palmitic acid to trigger cytokine release is not dependent on the presence of microglia. Finally, data show that the essential ω-3 fatty acid docosahexaenoic acid acts in a dose-dependent manner to prevent the actions of palmitic acid on inflammatory signaling in astrocytes. Collectively, these data demonstrate the ability of saturated fatty acids to induce astrocyte inflammation in vitro. These data thus raise the possibility that high levels of circulating saturated fatty acids could cause reactive gliosis and brain inflammation in vivo, and could potentially participate in the reported adverse neurologic consequences of obesity and metabolic syndrome.
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Astrocitos/efectos de los fármacos , Citocinas/metabolismo , Ácidos Grasos/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Animales Recién Nacidos , Encéfalo/citología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Ensayo de Inmunoadsorción Enzimática , Ácidos Grasos/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ácido Oléico/farmacología , Ácido Palmítico/farmacología , Ratas , Ratas Sprague-Dawley , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
Driving simulators may be an effective means of assessing driving performance, however many are cost-prohibitive. The present pilot study examined whether a novel, cost-effective driving simulator (Assetto Corsa (AC)) may be useful in the evaluation of older adults' driving performance, and explore associations among various driving safety indicators. A community sample of older adults completed a battery of cognitive measures, several self-reported driving measures, and a novel driving simulator task (AC). Simple attention, executive functioning, and processing speed were associated with simulator performance variables. Lower self-rated driving safety was associated with slower simulated driving. Additionally, several cognitive domains were associated with perceptions about driving-related safety and driving-related legal repercussions (e.g., traffic tickets). Findings suggested that associations between cognitive tests with AC were less robust than those found in other simulator studies. Novel associations between cognitive performance and self-reported driving were identified; however, given the small sample size of this study, such associations should be explored further.
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Conducción de Automóvil , Función Ejecutiva , Anciano , Atención , Simulación por Computador , Humanos , Pruebas Neuropsicológicas , Proyectos PilotoRESUMEN
BACKGROUND AND OBJECTIVES: Over 10,000 people a day turn 65 in the United States. For many older adults, driving represents an essential component of independence and is one of the most important factors in overall mobility. Recent survey studies in older adults suggest that up to 60% of older adult drivers with mild cognitive impairment, and up to 30% with dementia, continue to drive. The purpose of this review is to provide a comprehensive and detailed resource on the topics of cognition and driving for clinicians, researchers, and policymakers working on efforts related to older adult drivers. RESEARCH DESIGN AND METHODS: Publications on PubMed and Medline and discussions with experts working in geriatrics, technology, driving policy, psychology, and diverse aspects of driving performance were utilized to inform the current review. RESULTS: Research indicates that there is a complex and inverse correlation between multiple cognitive measures, driving performance, and risky driving behaviors. The fragmented nature of available peer-reviewed literature, and a reliance on correlative data, do not currently allow for the identification of the temporal and reciprocal nature of the interplay between cognition and driving endpoints. DISCUSSION AND IMPLICATIONS: There are currently no widely accepted definitions, conceptual models, or uniform set of analyses for conducting geriatric research that is focused on driving. Establishing conventions for conducting research that harmonizes the fields of geriatrics, cognition, and driving research is critical for the development of the evidence base that will inform clinical practice and road safety policy.
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Subject motion is a well-known confound in resting-state functional MRI (rs-fMRI) and the analysis of functional connectivity. Consequently, several clean-up strategies have been established to minimize the impact of subject motion. Physiological signals in response to cardiac activity and respiration are also known to alter the apparent rs-fMRI connectivity. Comprehensive comparisons of common noise regression techniques showed that the "Independent Component Analysis based strategy for Automatic Removal of Motion Artifacts" (ICA-AROMA) was a preferred pre-processing technique for teenagers and adults. However, motion and physiological noise characteristics may differ substantially for older adults. Here, we present a comprehensive comparison of noise-regression techniques for older adults from a large multi-site clinical trial of exercise and intensive pharmacological vascular risk factor reduction. The Risk Reduction for Alzheimer's Disease (rrAD) trial included hypertensive older adults (60-84 years old) at elevated risk of developing Alzheimer's Disease (AD). We compared the performance of censoring, censoring combined with global signal regression, non-aggressive and aggressive ICA-AROMA, as well as the Spatially Organized Component Klassifikator (SOCK) on the rs-fMRI baseline scans from 434 rrAD subjects. All techniques were rated based on network reproducibility, network identifiability, edge activity, spatial smoothness, and loss of temporal degrees of freedom (tDOF). We found that non-aggressive ICA-AROMA did not perform as well as the other four techniques, which performed table with marginal differences, demonstrating the validity of these techniques. Considering reproducibility as the most important factor for longitudinal studies, given low false-positive rates and a better preserved, more cohesive temporal structure, currently aggressive ICA-AROMA is likely the most suitable noise regression technique for rs-fMRI studies of older adults.