While considerable knowledge has been gained through the use of established cognitive and motor assessment tools, there is a considerable interest and need for the development of a battery of ...reliable and validated assessment tools that provide real-time and remote analysis of cognitive and motor function in the elderly. Smartphones appear to be an obvious choice for the development of these "next-generation" assessment tools for geriatric research, although to date no studies have reported on the use of smartphone-based applications for the study of cognition in the elderly. The primary focus of the current study was to assess the feasibility, reliability, and validity of a smartphone-based application for the assessment of cognitive function in the elderly. A total of 57 non-demented elderly individuals were administered a newly developed smartphone application-based Color-Shape Test (CST) in order to determine its utility in measuring cognitive processing speed in the elderly. Validity of this novel cognitive task was assessed by correlating performance on the CST with scores on widely accepted assessments of cognitive function. Scores on the CST were significantly correlated with global cognition (Mini-Mental State Exam: r = 0.515, p<0.0001) and multiple measures of processing speed and attention (Digit Span: r = 0.427, p<0.0001; Trail Making Test: r = -0.651, p<0.00001; Digit Symbol Test: r = 0.508, p<0.0001). The CST was not correlated with naming and verbal fluency tasks (Boston Naming Test, Vegetable/Animal Naming) or memory tasks (Logical Memory Test). Test re-test reliability was observed to be significant (r = 0.726; p = 0.02). Together, these data are the first to demonstrate the feasibility, reliability, and validity of using a smartphone-based application for the purpose of assessing cognitive function in the elderly. The importance of these findings for the establishment of smartphone-based assessment batteries of cognitive and motor function in the elderly is discussed.
J. Neurochem. (2012) 120, 1060–1071.
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.
The good fat, the bad fat, and the brain Obesity and metabolic syndrome detrimentally affect the brain through unknown mechanisms. This paper demonstrates the ability of saturated fatty acids to trigger cytokine release from cultured astrocytes, and the ability of ω‐3 unsaturated fatty acids to block cytokine release. These data suggest that circulating saturated fatty acids could cause brain inflammation and thus participate in the adverse neurologic consequences of metabolic syndrome
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.
► Review of the role of oxidative stress in neurodegenerative disease. ► Sources of cerebral endothelial cell oxidative stress are discussed. ► Effects of oxidative stress on cerebral endothelial cells are discussed. ► Some of the current antioxidant treatments are reviewed (pharmaceutical and dietary). ► The potential use of antioxidants targeted to cerebrovascular oxidative stress is discussed.
J. Neurochem. (2010) 114, 1581-1589. Long term consumption of a high fat diet (HFD) contributes to increased morbidity and mortality. Yet the specific effects of HFD consumption on brain aging are ...poorly understood. In the present study 20-month old male C57Bl/6 mice were fed either 'western diet' (41% fat), very high fat lard diet (60% fat), or corresponding control diets for 16 weeks and then assessed for changes in metabolism and brain homeostasis. Although both HFDs increased adiposity and fasting blood glucose, only the high fat lard diet increased age-related oxidative damage (protein carbonyls) and impaired retention in the behavioral test. This selective increase in oxidative damage and cognitive decline was also associated with a decline in NF-E2-related factor 2 (Nrf2) levels and Nrf2 activity, suggesting a potential role for decreased antioxidant response. Taken together, these data suggest that while adiposity and insulin resistance following HFD consumption are linked to increased morbidity, the relationship between these factors and brain homeostasis during aging is not a linear relationship. More specifically, these data implicate impaired Nrf2 signaling and increased cerebral oxidative stress as mechanisms underlying HFD-induced declines in cognitive performance in the aged brain.
Background and purpose
Neurological manifestations in coronavirus disease (COVID)‐2019 may adversely affect clinical outcomes. Severe COVID‐19 and uremia are risk factors for neurological ...complications. However, the lack of insight into their pathogenesis, particularly with respect to the role of the cytokine release syndrome (CRS), is currently hampering effective therapeutic interventions. The aims of this study were to describe the neurological manifestations of patients with COVID‐19 and to gain pathophysiological insights with respect to CRS.
Methods
In this longitudinal study, we performed extensive clinical, laboratory and imaging phenotyping in five patients admitted to our renal unit.
Results
Neurological presentation included confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism. Notably, neurological disturbances were accompanied by laboratory evidence of CRS. Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) was undetectable in the cerebrospinal fluid (CSF). Hyperalbuminorrachia and increased levels of the astroglial protein S100B were suggestive of blood−brain barrier (BBB) dysfunction. Brain magnetic resonance imaging findings comprised evidence of acute leukoencephalitis (n = 3, one of whom had a hemorrhagic form), cytotoxic edema mimicking ischaemic stroke (n = 1), or normal results (n = 2). Treatment with corticosteroids and/or intravenous immunoglobulins was attempted, resulting in rapid recovery from neurological disturbances in two cases. SARS‐CoV2 was undetectable in 88 of the 90 patients with COVID‐19 who underwent Reverse Transcription‐PCR testing of CSF.
Conclusions
Patients with COVID‐19 can develop neurological manifestations that share clinical, laboratory and imaging similarities with those of chimeric antigen receptor T‐cell‐related encephalopathy. The pathophysiological underpinnings appear to involve CRS, endothelial activation, BBB dysfunction, and immune‐mediated mechanisms.
Fear conditioning is widely employed to study dysregulations of the fear system. The repeated presentation of a conditioned stimulus in the absence of a reinforcer leads to a decrease in fear ...responding—a phenomenon known as extinction. From a translational perspective, identifying whether an individual might respond well to extinction prior to intervention could prove important to treatment outcomes. Here, we test the hypothesis that CO
2
reactivity predicts extinction phenotype in rats, and that variability in CO
2
reactivity as well as extinction long-term memory (LTM) significantly predicts orexin activity in the lateral hypothalamus (LH). Our results validate a rat model of CO
2
reactivity and show that subcomponents of behavioral reactivity following acute CO
2
exposure explain a significant portion of the variance in extinction LTM. Furthermore, we show evidence that variability in CO
2
reactivity is also significantly predictive of orexin activity in the LH, and that orexin activity, in turn, significantly accounts for LTM variance. Our findings open the possibility that we may be able to use CO
2
reactivity as a screening tool to determine if individuals are good candidates for an extinction/exposure-based approach.
Developing measures to detect preclinical Alzheimer's Disease is vital, as prodromal stage interventions may prove more efficacious in altering the disease's trajectory. Gait changes may serve as a ...useful clinical heuristic that precedes cognitive decline. This study provides the first systematic investigation of gait characteristics relationship with relevant demographic, physical, genetic (Apolipoprotein E genotype), and health risk factors in non-demented older adults during a cognitive-load dual task walking condition.
The GAITRite system provided objective measurement of gait characteristics in APOE-e4 "carriers" (n = 75) and "non-carriers" (n = 224). Analyses examined stride length and step time gait characteristics during simple and dual-task (spelling five-letter words backwards) conditions in relation to demographic, physical, genetic, and health risk factors.
Slower step time and shorter stride length associated with older age, greater health risk, and worse physical performance (ps < .05). Men and women differed in height, gait characteristics, health risk factors and global cognition (ps < .05). APOE-e4 associated with a higher likelihood of hypercholesterolemia and overall illness index scores (ps < .05). No genotype-sex interactions on gait were found. APOE-e4 was linked to shorter stride length and greater dual-task related disturbances in stride length.
Stride length has been linked to heightened fall risk, attention decrements and structural brain changes in older adults. Our results indicate that stride length is a useful behavioral marker of cognitive change that is associated with genetic risk for AD. Sex disparities in motor decline may be a function of health risk factors.
Nearly two-thirds of the population in the United States is overweight or obese, and this unprecedented level of obesity will undoubtedly have a profound impact on overall health, although little is ...currently known about the effects of obesity on the brain. The objective of this study was to investigate cerebral oxidative stress and cognitive decline in the context of diet-induced obesity (DIO). We demonstrate for the first time that DIO induces higher levels of reactive oxygen species (ROS) in the brain and promotes cognitive impairment. Importantly, we also demonstrate for the first time in these studies that both body weight and adiposity are tightly correlated with the level of ROS. Interestingly, ROS were not correlated with cognitive decline in this model. Alterations in the antioxidant/detoxification Nrf2 pathway, superoxide dismutase, and catalase activity levels were not significantly altered in response to DIO. However, a significant impairment in glutathione peroxidase was observed in response to DIO. Taken together, these data demonstrate for the first time that DIO increases the levels of total and individual ROS in the brain and highlight a direct relationship between the amount of adiposity and the level of oxidative stress within the brain. These data have important implications for understanding the negative effects of obesity on the brain and are vital to understanding the role of oxidative stress in mediating the effects of obesity on thebrain.
Les macrophages sont des cellules de l’immunité innée et sont localisés dans la majorité des organes du corps, présentant des fonctions spécifiques dépendant de leur lieu de résidence. Il est ...aujourd’hui admis qu’en plus de leur fonction immunologique, les macrophages ont aussi des rôles clés dans le développement, le maintien de l’homéostasie et la régénération tissulaire, contribuant ainsi au bon fonctionnement de divers organes. Le testicule est considéré comme un organe immuno-privilégié et par conséquent, a cette nécessité de protéger de tous contacts les spermatozoïdes des cellules immunitaires, qui pourraient induire une auto-immunité et donc l’infertilité. Cependant les macrophages testiculaires (tMφ) représentent la plus abondante des populations du système immunitaire dans les testicules des mammifères et contribuent à maintenir ce statut d’organe immuno-privilégié. Pour ces raisons, les tMφ peuvent être considérés comme des “gardiens de la fertilité”. Nous avons caractérisé deux différentes populations de macrophages, nommées interstitielles et péritubulaires et étudié leur origine, émergence, développement ainsi que leur mode de maintenance dans les testicules. En combinant des méthodes de traçage cellulaire et un modèle de transfert adoptif dans des souriceaux, nous avons démontré que les macrophages d’origine embryonnaire contribuaient exclusivement à la population de tMφ interstitielle dès la naissance. Nous avons aussi montré que les tMφ péritubulaires proviennent exclusivement de la moelle osseuse et n’apparaissent que deux semaines après la naissance des souriceaux, soit l’équivalent de la puberté. De façon surprenante, une fois établies dans les testicules, les deux populations de tMφ y restent toute leur vie sans être renouvelées.
Antibody-based cancer drugs that target the checkpoint proteins CTLA-4, PD-1 and PD-L1 provide marked improvement in some patients with deadly diseases such as lung cancer and melanoma. However, most ...patients are either unresponsive or relapse following an initial response, underscoring the need for further improvement in immunotherapy. Certain drugs induce immunogenic cell death (ICD) in tumor cells in which the dying cells promote immunologic responses in the host that may enhance the in vivo activity of checkpoint antibodies. Sphingolipid metabolism is a key pathway in cancer biology, in which ceramides and sphingosine 1-phosphate (S1P) regulate tumor cell death, proliferation and drug resistance, as well as host inflammation and immunity. In particular, sphingosine kinases are key sites for manipulation of the ceramide/S1P balance that regulates tumor cell proliferation and sensitivity to radiation and chemotherapy. We and others have demonstrated that inhibition of sphingosine kinase-2 by the small-molecule investigational drug opaganib (formerly ABC294640) kills tumor cells and increases their sensitivities to other drugs and radiation. Because sphingolipids have been shown to regulate ICD, opaganib may induce ICD and improve the efficacy of checkpoint antibodies for cancer therapy. This was demonstrated by showing that in vitro treatment with opaganib increases the surface expression of the ICD marker calreticulin on a variety of tumor cell types. In vivo confirmation was achieved using the gold standard immunization assay in which B16 melanoma, Lewis lung carcinoma (LLC) or Neuro-2a neuroblastoma cells were treated with opaganib in vitro and then injected subcutaneously into syngeneic mice, followed by implantation of untreated tumor cells 7 days later. In all cases, immunization with opaganib-treated cells strongly suppressed the growth of subsequently injected tumor cells. Interestingly, opaganib treatment induced crossover immunity in that opaganib-treated B16 cells suppressed the growth of both untreated B16 and LLC cells and opaganib-treated LLC cells inhibited the growth of both untreated LLC and B16 cells. Next, the effects of opaganib in combination with a checkpoint antibody on tumor growth in vivo were assessed. Opaganib and anti-PD-1 antibody each slowed the growth of B16 tumors and improved mouse survival, while the combination of opaganib plus anti-PD-1 strongly suppressed tumor growth and improved survival (
< 0.0001). Individually, opaganib and anti-CTLA-4 antibody had modest effects on the growth of LLC tumors and mouse survival, whereas the combination of opaganib with anti-CTLA-4 substantially inhibited tumor growth and increased survival (
< 0.001). Finally, the survival of mice bearing B16 tumors was only marginally improved by opaganib or anti-PD-L1 antibody alone but was nearly doubled by the drugs in combination (
< 0.005). Overall, these studies demonstrate the ability of opaganib to induce ICD in tumor cells, which improves the antitumor activity of checkpoint antibodies.
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