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A Comprehensive Review of Non-Steroidal Anti-Inflammatory Drug Use in The Elderly
Supakanya Wongrakpanich,Amaraporn Wongrakpanich,Katie Melhado,Janani Rangaswami
A&D    2018, 9 (1): 143-150.   DOI: 10.14336/AD.2017.0306
Abstract1678)   HTML20)    PDF(pc) (874KB)(1123)       Save

NSAIDs, non-steroidal anti-inflammatory drugs, are one of the most commonly prescribed pain medications. It is a highly effective drug class for pain and inflammation; however, NSAIDs are known for multiple adverse effects, including gastrointestinal bleeding, cardiovascular side effects, and NSAID induced nephrotoxicity. As our society ages, it is crucial to have comprehensive knowledge of this class of medication in the elderly population. Therefore, we reviewed the pharmacodynamics and pharmacokinetics, current guidelines for NSAIDs use, adverse effect profile, and drug interaction of NSAIDs and commonly used medications in the elderly.

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Role of Dietary Protein and Muscular Fitness on Longevity and Aging
Barbara Strasser,Konstantinos Volaklis,Dietmar Fuchs,Martin Burtscher
A&D    2018, 9 (1): 119-132.   DOI: 10.14336/AD.2017.0202
Abstract1549)   HTML11)    PDF(pc) (936KB)(599)       Save

Muscle atrophy is an unfortunate effect of aging and many diseases and can compromise physical function and impair vital metabolic processes. Low levels of muscular fitness together with insufficient dietary intake are major risk factors for illness and mortality from all causes. Ultimately, muscle wasting contributes significantly to weakness, disability, increased hospitalization, immobility, and loss of independence. However, the extent of muscle wasting differs greatly between individuals due to differences in the aging process per se as well as physical activity levels. Interventions for sarcopenia include exercise and nutrition because both have a positive impact on protein anabolism but also enhance other aspects that contribute to well-being in sarcopenic older adults, such as physical function, quality of life, and anti-inflammatory state. The process of aging is accompanied by chronic immune activation, and sarcopenia may represent a consequence of a counter-regulatory strategy of the immune system. Thereby, the kynurenine pathway is induced, and elevation in the ratio of kynurenine to tryptophan concentrations, which estimates the tryptophan breakdown rate, is often linked with inflammatory conditions and neuropsychiatric symptoms. A combined exercise program consisting of both resistance-type and endurance-type exercise may best help to ameliorate the loss of skeletal muscle mass and function, to prevent muscle aging comorbidities, and to improve physical performance and quality of life. In addition, the use of dietary protein supplementation can further augment protein anabolism but can also contribute to a more active lifestyle, thereby supporting well-being and active aging in the older population.

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Transcultural Adaptation and Validation of the Spanish Bristol Foot Score (BFS-S)
Emmanuel Navarro-Flores, Marta Elena Losa-Iglesias, Ricardo Becerro-de-Bengoa-Vallejo, Daniel Lopez-Lopez, Juan Manuel Vilar-Fernandez, Patricia Palomo-Lopez, Cesar Calvo-Lobo
Aging and disease    2018, 9 (5): 861-868.   DOI: 10.14336/AD.2017.1215
Abstract1209)   HTML2)    PDF(pc) (428KB)(185)       Save

The Bristol Foot Score is considered an instrument for measuring the impact of foot problems and pain. It was developed and validated in United Kingdom. Therefore, this aim was to perform the transcultural adaptation and validation of the Spanish version. The recommended forward/backward translation protocol was applied for the procedure of translation, transcultural adaptation and validation to Spain. Considering each domain and question, internal consistency and reliability were analyzed through the Crombach alpha (α) and intraclass correlation coefficient (ICC) with a 95% confidence interval (95% CI). A very good internal consistency was shown for the 3 domains: concern and pain showed a Cronbach of 0.896, footwear and general foot health of 0.790, mobility 0.887. Each question had a very good test-retest reliability, ranged from 0.721 to 0.963 with no systematic differences (P>0.05) in each question of the Spanish Bristol Foot Score (BFS-S) questionnaire. The test-retest reliability was excellent (ICC 95%): concern and foot pain 0.950 (0.913-0971); footwear and general foot health 0.914 (0.851-0.950), mobility 0.973 (0.953-0.984) and there were no sistematic differences in any domain (P > 0.05). The BFS-S was shown to be a valid and reliable tool with an acceptable use in the Spanish population.

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Acute Sarcopenia Secondary to Hospitalisation - An Emerging Condition Affecting Older Adults
Carly Welch,Zaki K. Hassan-Smith,Carolyn A. Greig,Janet M. Lord,Thomas A. Jackson
A&D    2018, 9 (1): 151-164.   DOI: 10.14336/AD.2017.0315
Abstract1184)   HTML6)    PDF(pc) (837KB)(527)       Save

There has been increasing interest and research into sarcopenia in community-dwelling older adults since the European Working Group on Sarcopenia in Older People (EWGSOP) agreed a consensus definition in 2010. Sarcopenia has been defined as loss of muscle mass with loss of muscle function (strength or physical performance), with measurements two Standard Deviations (SDs) below the mean of a young reference population. This definition does not necessitate longitudinal measurements, or the absence of acute illness and diagnosis can be made from single measurements. We hypothesise that hospitalisation, due to a combination of acute inflammatory burden and muscle disuse, leads to an acute decline in muscle mass and function and may lead to some individuals meeting criteria for sarcopenia, acutely, based on the EWGSOP definition. This may be partially recoverable or may lead to increased risk of developing sarcopenia long-term. We have denoted the term “acute sarcopenia” to refer to acute loss of muscle mass and function associated with hospitalisation. This review discusses some of the current available research in this context and also identifies some of the knowledge gaps and potential areas for future research.

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CLARITY for High-resolution Imaging and Quantification of Vasculature in the Whole Mouse Brain
Lin-Yuan Zhang,Pan Lin,Jiaji Pan,Yuanyuan Ma,Zhenyu Wei,Lu Jiang,Liping Wang,Yaying Song,Yongting Wang,Zhijun Zhang,Kunlin Jin,Qian Wang,Guo-Yuan Yang
A&D    2018, 9 (2): 262-272.   DOI: 10.14336/AD.2017.0613
Abstract1104)   HTML3)    PDF(pc) (1299KB)(590)       Save

Elucidating the normal structure and distribution of cerebral vascular system is fundamental for understanding its function. However, studies on visualization and whole-brain quantification of vasculature with cellular resolution are limited. Here, we explored the structure of vasculature at the whole-brain level using the newly developed CLARITY technique. Adult male C57BL/6J mice undergoing transient middle cerebral artery occlusion and Tie2-RFP transgenic mice were used. Whole mouse brains were extracted for CLARITY processing. Immunostaining was performed to label vessels. Customized MATLAB code was used for image processing and quantification. Three-dimensional images were visualized using the Vaa3D software. Our results showed that whole mouse brain became transparent using the CLARITY method. Three-dimensional imaging and visualization of vasculature were achieved at the whole-brain level with a 1-μm voxel resolution. The quantitative results showed that the fractional vascular volume was 0.018 ± 0.004 mm3 per mm3, the normalized vascular length was 0.44 ± 0.04 m per mm3, and the mean diameter of the microvessels was 4.25 ± 0.08 μm. Furthermore, a decrease in the fractional vascular volume and a decrease in the normalized vascular length were found in the penumbra of ischemic mice compared to controls (p < 0.05). In conclusion, CLARITY provides a novel approach for mapping vasculature in the whole mouse brain at cellular resolution. CLARITY-optimized algorithms facilitate the assessment of structural change in vasculature after brain injury.

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The Study of Rhabdomyolysis in the Elderly: An Epidemiological Study and Single Center Experience
Supakanya Wongrakpanich,Christos Kallis,Prithiv Prasad,Janani Rangaswami,Andrew Rosenzweig
A&D    2018, 9 (1): 1-7.   DOI: 10.14336/AD.2017.0304
Abstract969)   HTML13)    PDF(pc) (650KB)(546)       Save

Rhabdomyolysis is a syndrome caused by injury to skeletal muscle. There is limited data of rhabdomyolysis in the elderly. The objective of this study is to investigate demographic data, etiologies, laboratory values, prognostic factors, and mortality of rhabdomyolysis in the geriatric population. A 4-years retrospective chart review study was conducted. Our inclusion criteria were age above 65 years and creatinine kinase level excess five times of normal upper limit. Among 167 patients, 47.3% were male. The median age at diagnosis was 80.11 (66-101) years. The duration of follow up in the study ranged from 0 to 48 months. Fall (with or without immobilization) was the most frequent cause of rhabdomyolysis in 56.9%. The mean baseline glomerular filtration rate (GFR), GFR at diagnosis, and peak decline in GFR was 76.94, 48.96, and 54.41 cc/min respectively. The mean CK at diagnosis and peak CK was 5097.22 and 6320.07. There were 45 deaths (21%) over the span of 4 years. Multivariate analysis demonstrated that number of medications pre-admission (Meds No.), peak decline in GFR, and acute kidney injury (AKI) are independent predictors for overall survival for rhabdomyolysis in the elderly. To our knowledge, this is the first epidemiological study of rhabdomyolysis in the elderly. Falls (with and without immobilization) were the most common etiology. Meds No. (>8), peak decline in GFR (<30 cc/min), and evidence of AKI are associated with shorter overall survival and can serve as potential independent prognostic markers for rhabdomyolysis in elderly patients.

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Effect of Rhythmic Auditory Cueing on Aging Gait: A Systematic Review and Meta-Analysis
Shashank Ghai, Ishan Ghai, Alfred O. Effenberg
Aging and disease    2018, 9 (5): 901-923.   DOI: 10.14336/AD.2017.1031
Abstract836)   HTML4)    PDF(pc) (844KB)(373)       Save

Rhythmic auditory cueing has been widely used in gait rehabilitation over the past decade. The entrainment effect has been suggested to introduce neurophysiological changes, alleviate auditory-motor coupling and reduce cognitive-motor interferences. However, a consensus as to its influence over aging gait is still warranted. A systematic review and meta-analysis was carried out to analyze the effects of rhythmic auditory cueing on spatiotemporal gait parameters among healthy young and elderly participants. This systematic identification of published literature was performed according to PRISMA guidelines, from inception until May 2017, on online databases: Web of science, PEDro, EBSCO, MEDLINE, Cochrane, EMBASE, and PROQUEST. Studies were critically appraised using PEDro scale. Of 2789 records, 34 studies, involving 854 (499 young/355 elderly) participants met our inclusion criteria. The meta-analysis revealed enhancements in spatiotemporal parameters of gait i.e. gait velocity (Hedge’s g: 0.85), stride length (0.61), and cadence (1.1), amongst both age groups. This review, for the first time, evaluates the effects of auditory entrainment on aging gait and discusses its implications under higher and lower information processing constraints. Clinical implications are discussed with respect to applications of auditory entrainment in rehabilitation settings.

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Anserine/Carnosine Supplementation Preserves Blood Flow in the Prefrontal Brain of Elderly People Carrying APOE e4
Qiong Ding,Kitora Tanigawa,Jun Kaneko,Mamoru Totsuka,Yoshinori Katakura,Etsuko Imabayashi,Hiroshi Matsuda,Tatsuhiro Hisatsune
A&D    2018, 9 (3): 334-345.   DOI: 10.14336/AD.2017.0809
Abstract734)   HTML10)    PDF(pc) (789KB)(324)       Save

In a previously reported double-blind, randomized controlled trial (RCT), we demonstrated that daily supplementation with anserine (750 mg) and carnosine (250 mg) improves brain blood flow and memory function in elderly people. Here, we conducted a sub-analysis of MRI data and test scores from the same RCT to determine whether anserine/carnosine supplementation specifically benefits elderly people carrying the APOE e4 allele, which is a risk gene for accelerated brain aging and for the onset of Alzheimer’s Disease. We collected data from 68 participants aged 65 years or older who received anserine/carnosine supplementation (ACS) or placebo for 12 months. Subjects were assessed at the start and end of the trial using several neuropsychological tests, including the Wechsler Memory Scale-Logical Memory (WMS-LM). We also collected two types of MRI data, arterial spin labeling (ASL) and diffusion tensor imaging (DTI) at the start and end of the trial. We found that ACS significantly preserved verbal memory (WMS-LM, F[1,65] = 4.2003, p = 0.0445) and blood flow at frontal areas of the brain (FWEcluster level, p < 0.001). Sub-analysis based on the APOE4 genotype showed a significant preservation of blood flow (p = 0.002, by ASL analysis) and white-matter microstructure (p = 0.003, by DTI analysis) at prefrontal areas in APOE4+ subjects in the active group, while there was no significant difference between APOE4- subjects in the active and placebo groups. The effect of ACS in preserving brain structure and function in elderly people carrying APOE4 should be verified by further studies.

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Causes of Death in Chinese Patients with Multiple System Atrophy
LingYu Zhang,Bei Cao,Yutong Zou,Qian-Qian Wei,RuWei Ou,Wanglin Liu,Bi Zhao,Jing Yang,Ying Wu,HuiFang Shang
A&D    2018, 9 (1): 102-108.   DOI: 10.14336/AD.2017.0711
Abstract691)   HTML3)    PDF(pc) (711KB)(200)       Save

The objective of this study was to explore the causes of death in Chinese patients with multiple system atrophy (MSA) as well as differences in the cause of death according to sex, subtype, disease onset, and whether the disease was accompanied by nocturnal stridor. A total of 131 MSA patients were enrolled and followed up once every year until their deaths. Clinical information was collected by neurologists, and the cause of death of the MSA patients was obtained from the patients’ relatives or caregivers. The current study included 62 MSA with predominant parkinsonism (MSA-P) and 69 MSA with predominant cerebellar ataxia (MSA-C) patients. Median survival time from disease onset to death of the MSA patients was 5.59 years. The most common cause of death was respiratory infection (65.6%). The second most common cause of death was sudden death (14.5%). Other causes included nutritional disorder due to dysphagia (9.2%), urinary tract infection (3.1%), suicide (2.3%), choking (1.5%), cerebrovascular accident (1.5%), myocardial infarction (1.5%), and lymphoma (0.8%). We found that sudden death was more likely to occur in patients with nocturnal stridor than in those without (P<0.001). There were no significant differences in the cause of death according to subtype, sex, or onset symptoms (autonomic failure or motor symptoms). Sudden death is a relatively common cause of death in MSA patients, second only to respiratory infection, especially in patients with nocturnal stridor. The information provided by our study may help to provide better medical care to MSA patients.

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Aged Mice are More Resistant to Influenza Virus Infection due to Reduced Inflammation and Lung Pathology
Jiao Lu,Xuefeng Duan,Wenming Zhao,Jing Wang,Haoyu Wang,Kai Zhou,Min Fang
A&D    2018, 9 (3): 358-373.   DOI: 10.14336/AD.2017.0701
Abstract690)   HTML6)    PDF(pc) (1553KB)(419)       Save

Immune responses are a double-edged sword. Effective and appropriate immune responses capable of controlling viral infection while also largely preserving tissue integrity, are critical for host survival. Too strong immune responses might result in immune pathology, while too weak immune responses might cause viral persistence. Physiologic ageing is accompanied with a decline in the normal functioning of the immune system, which is termed as "immunosenescence". We show that aged mice (16-19 months old) are more resistant to influenza A virus (IAV) infection than the young mice. Strong immune responses in the young mice after IAV infection result in faster clearance of virus, but also cause severe lung injury and higher mortality rate. While in the aged mice, the delayed and milder immune responses contribute to reduced pulmonary damage, and are still capable to clear the infection even with a slower kinetics, displaying a more resistant phenotype during IAV infection. Hence, our work demonstrates that moderate immune responses as a decline with ageing in the aged mice balance the immune pathology and viral clearance, might be beneficial for the host during certain circumstances. Our results provide important insight to our basic knowledge of immunosenescence and immune defenses to invading pathogens. Further, our results indicate that age factors should be considered when investigating the vaccination and therapeutic strategies for severe IAV infection.

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Cardiovascular Risk Factors Are Correlated with Low Cognitive Function among Older Adults Across Europe Based on The SHARE Database
Joana Lourenco,Antonio Serrano,Alice Santos-Silva,Marcos Gomes,Claudia Afonso,Paula Freitas,Constanca Paul,Elisio Costa
A&D    2018, 9 (1): 90-101.   DOI: 10.14336/AD.2017.0128
Abstract652)   HTML6)    PDF(pc) (1099KB)(345)       Save

Increased life expectancy is associated with a high prevalence of chronic, non-communicable diseases including cognitive decline and dementia. The purpose of this study was to evaluate the prevalence of cognitive impairment using three cognitive abilities (verbal fluency, numeracy and perceived memory) and their association with cardiovascular risk factors in seniors across Europe. Data from participants in wave 4 of the SHARE (Survey of Health, Ageing, and Retirement in Europe) database was used. Cognitive performance in perceived memory, verbal fluency and numeracy was evaluated using simple tests and a memory complaints questionnaire. Clinical and sociodemographic variables were also studied for potential associations. Standardised prevalence rates of cognitive impairment based on age and gender were calculated by country. The prevalence of cognitive impairment was 28.02% for perceived memory, 27.89% for verbal fluency and 20.75% for numeracy throughout the 16 evaluated countries. Years of education, being a current or former smoker, number of chronic diseases, diabetes or hyperglycemia, heart attack and stroke were all independent variables associated with impairment in the three studied cognitive abilities. We also found independent associations between physical inactivity and verbal fluency and numeracy impairment, as well as hypertension and perceived memory impairment. Lower performance in the evaluated cognitive abilities and higher memory complaints are highly prevalent, have a heterogeneous distribution across Europe, and are associated with multiple factors, most of which are potentially preventable or treatable, especially cardiovascular risk factors.

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Novel Modification of Potassium Chloride Induced Cardiac Arrest Model for Aged Mice
Huaqin Liu,Zhui Yu,Ying Li,Bin Xu,Baihui Yan,Wulf Paschen,David S Warner,Wei Yang,Huaxin Sheng
A&D    2018, 9 (1): 31-39.   DOI: 10.14336/AD.2017.0221
Abstract622)   HTML8)    PDF(pc) (1158KB)(272)       Save

Experimental cardiac arrest (CA) in aging research is infrequently studied in part due to the limitation of animal models. We aimed to develop an easily performed mouse CA model to meet this need. A standard mouse KCl-induced CA model using chest compressions and intravenous epinephrine for resuscitation was modified by blood withdrawal prior to CA onset, so as to decrease the requisite KCl dose to induce CA by decreasing the circulating blood volume. The modification was then compared to the standard model in young adult mice subjected to 8 min CA. 22-month old mice were then subjected to 8 min CA, resuscitated, and compared to young adult mice. Post-CA functional recovery was evaluated by measuring spontaneous locomotor activity pre-injury, and on post-CA days 1, 2, and 3. Neurological score and brain histology were examined on day 3. Brain elF2α phosphorylation levels were measured at 1 h to verify tissue stress. Compared to the standard model, the modification decreased cardiopulmonary resuscitation duration and increased 3-day survival in young mice. For aged mice, survival was 100 % at 24 h and 54% at 72 h. Neurological deficit was present 3 days post-CA, although more severe versus young mice. Mild neuronal necrosis was present in the cortex and hippocampus. The modified model markedly induced elF2α phosphorylation in both age groups. This modified procedure makes the CA model feasible in aged mice and provides a practical platform for understanding injury mechanisms and developing therapeutics for elderly patients.

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Kidney Disease in Elderly: Importance of Collaboration between Geriatrics and Nephrology
Faheemuddin Azher Ahmed
A&D    2018, 9 (4): 745-747.   DOI: 10.14336/AD.2018.0223
Abstract571)   HTML0)    PDF(pc) (259KB)(77)       Save

The population in the United States is aging and presents many challenges in the healthcare world. According to the report released by United States Census Bureau in June 2017, there are around 50 million residents aged 65 years and over as of 2016. Among the multiple healthcare challenges, kidney disease is a significant one because of its high burden, high cost and low awareness. Medicare spending on chronic kidney disease for 65 plus aged patients exceeded $ 50 billion in 2013. Different studies based on different calculations have estimated that at least one-third of chronic kidney disease patients are aged above 65 years. Most of the chronic kidney disease patients have multiple medical co-morbidities but geriatric syndromes are added factors that may be challenging for nephrologists. There is scarcity of well-trained geriatricians and in most instances, nephrologists take over the role of internist or geriatrician. This article outlines the need and importance of collaboration and coordination between geriatrics and nephrology for the best patient care and better healthcare outcomes.

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PARP-1 Inhibition Rescues Short Lifespan in Hyperglycemic C. Elegans And Improves GLP-1 Secretion in Human Cells
Qianghua Xia,Sumei Lu,Julian Ostrovsky,Shana E McCormack,Marni J Falk,Struan F. A Grant
A&D    2018, 9 (1): 17-30.   DOI: 10.14336/AD.2017.0230
Abstract560)   HTML15)    PDF(pc) (1317KB)(273)       Save

TCF7L2 is located at one of the most strongly associated type 2 diabetes loci reported to date. We previously reported that the most abundant member of a specific protein complex to bind across the presumed causal variant at this locus, rs7903146, was poly [ADP-ribose] polymerase type 1 (PARP-1). We analyzed the impact of PARP-1 inhibition on C. elegans health in the setting of hyperglycemia and on glucose-stimulated GLP-1 secretion in human intestinal cells. Given that high glucose concentrations progressively shorten the lifespan of C. elegans, in part by impacting key well-conserved insulin-modulated signaling pathways, we investigated the effect of PARP-1 inhibition with Olaparib on the lifespan of C. elegans nematodes under varying hyperglycemic conditions. Subsequently, we investigated whether Olaparib treatment had any effect on glucose-stimulated GLP-1 secretion in the human NCI-H716 intestinal cell line, a model system for the investigation of enteroendocrine function. Treatment with 100uM Olaparib in nematodes exposed to high concentrations of glucose led to significant lifespan rescue. The beneficial lifespan effect of Olaparib appeared to require both PARP-1 and TCF7L2, since treatment had no effect in hyperglycemic conditions in knock-out worm strains for either of these homologs. Further investigation using the NCI-H716 cells revealed that Olaparib significantly enhanced secretion of the incretin, GLP-1, plus the gene expression of TCF7L2, GCG and PC1. These data from studies in both C. elegans and a human cell line suggest that PARP-1 inhibition offers a novel therapeutic avenue to treat type 2 diabetes.

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Temporal Gene Expression Profiles after Focal Cerebral Ischemia in Mice
Chengjie Zhang,Yanbing Zhu,Song Wang,Zheng Zachory Wei,Michael Qize Jiang,Yongbo Zhang,Yuhualei Pan,Shaoxin Tao,Jimei Li,Ling Wei
A&D    2018, 9 (2): 249-261.   DOI: 10.14336/AD.2017.0424
Abstract529)   HTML7)    PDF(pc) (2155KB)(369)       Save

A cascade of pathological processes is triggered in the lesion area after ischemic stroke. Unfortunately, our understanding of these complicated molecular events is incomplete. In this investigation, we sought to better understand the detailed molecular and inflammatory events occurring after ischemic stroke. RNA-seq technology was used to identify whole gene expression profiles at days (D1, D3, D7, D14, D21) after focal cerebral ischemia in mice. Enrichment analyses based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms for the differentially expressed genes (DEGs) were then analyzed. Inflammation-related genes that were significantly expressed after stroke were selected for analysis and the temporal expression patterns of pro-inflammatory and anti-inflammatory genes were reported. These data illustrated that the number of DEGs increased accumulatively after cerebral ischemia. In summary, there were 1967 DEGs at D1, 2280 DEGs at D3, 2631 DEGs at D7, 5516 DEGs at D14 and 7093 DEGs at D21. The significantly enriched GO terms also increased. 58 GO terms and 18 KEGG pathways were significantly enriched at all inspected time points. We identified 87 DEGs which were functionally related to inflammatory responses. The expression levels of pro-inflammation related genes CD16, CD32, CD86, CD11b, Tumour necrosis factor α (TNF-α), Interleukin 1β (IL-1β) increased over time and peaked at D14. Anti-inflammation related genes Arginase 1 (Arg1) and Chitinase-like 3 (Ym1) peaked at D1 while IL-10, Transforming growth factor β (TGF-β) and CD206, which were induced at 1 day after cerebral ischemia, peaked by 7 to 14 days. These gene profile changes were potentially linked to microglia/macrophage phenotype changes and could play a role in astroglial activation. This study supplies new insights and detailed information on the molecular events and pathological mechanisms that occur after experimental ischemic stroke.

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The Prevalence of Frailty and its Associated Factors in Japanese Hemodialysis Patients
Hidemi Takeuchi,Haruhito A. Uchida,Yuki Kakio,Yuka Okuyama,Michihiro Okuyama,Ryoko Umebayashi,Kentaro Wada,Hitoshi Sugiyama,Ken Sugimoto,Hiromi Rakugi,Jun Wada
A&D    2018, 9 (2): 192-207.   DOI: 10.14336/AD.2017.0429
Abstract508)   HTML6)    PDF(pc) (1251KB)(253)       Save

The population undergoing dialysis is aging worldwide, particularly in Japan. The clinical condition of frailty is the most problematic expression in the elderly population. Potential pathophysiological factors of frailty present in patients with CKD and are accentuated in patients with ESRD. The aim of this study was to identify the prevalence and predictors of frailty in Japanese HD patients. This study was a multicenter, cross-sectional and observational investigation conducted at 6 institutions. To evaluate frailty, the modified Fried’s frailty phenotype adjusted for Japanese as the self-reported questionnaire was used. Of the 542 patients visiting each institution, 388 were enrolled in this study. In total, 26.0% of participants were categorized as not-frailty, 52.6% as pre-frailty and 21.4% as frailty. The prevalence of frailty increased steadily with age and was more prevalent in females than in males and the subjects with frailty received polypharmacy. A multivariate logistic regression analysis revealed that the factors independently associated with frailty were the following: female gender (odds ratio [OR] = 3.661, 95% confidence interval [CI] 1.398-9.588), age (OR = 1.065, 95% CI 1.014-1.119), age ≥ 75 years old (OR = 4.892, 95% CI 1.715-13.955), body mass index (BMI) < 18.5 (OR = 0.110, 95% CI 0.0293-0.416), number of medications being taken (OR = 1.351, 95% CI 1.163-1.570), diabetes mellitus (DM) (OR = 2.765, 95% CI 1.081-7.071) and MNA-SF ≤ 11 (OR = 7.405, 95% CI 2.732-20.072). Frailty was associated with the accumulation of risk factors. The prevalence of frailty in Japanese patients with HD was relatively lower than that previously reported in Western developed countries; however, it was extremely high compared to the general population regardless of age. Our findings suggest that frailty might be associated with an increase in the prevalence of adverse health outcomes in patients with HD.

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TOPK Promotes Microglia/Macrophage Polarization towards M2 Phenotype via Inhibition of HDAC1 and HDAC2 Activity after Transient Cerebral Ischemia
Ziping Han,Haiping Zhao,Zhen Tao,Rongliang Wang,Zhibin Fan,Yumin Luo,Yinghao Luo,Xunming Ji
A&D    2018, 9 (2): 235-248.   DOI: 10.14336/AD.2017.0328
Abstract486)   HTML8)    PDF(pc) (1521KB)(648)       Save

T-LAK-cell-originated protein kinase (TOPK) is a newly identified member of the mitogen-activated protein kinase family. Our previous study has showed that TOPK has neuroprotective effects against cerebral ischemia-reperfusion injury. Here, we investigated the involvement of TOPK in microglia/ macrophage M1/M2 polarization and the underlying epigenetic mechanism. The expression profiles, co-localization and in vivo interaction of TOPK, M1/M2 surface markers, and HDAC1/HDAC2 were detected after middle cerebral artery occlusion models (MCAO). We demonstrated that TOPK, the M2 surface markers CD206 and Arg1, p-HDAC1, and p-HDAC2 showed a similar pattern of in vivo expression over time after MCAO. TOPK co-localized with CD206, p-HDAC1, and p-HDAC2 positive cells, and was shown to bind to HDAC1 and HDAC2. In vitro study showed that TOPK overexpression in BV2 cells up-regulated CD206 and Arg1, and promoted the phosphorylation of HDAC1 and HDAC2. In addition, TOPK overexpression also prevented LPS plus IFN-γ-induced M1 transformation through reducing release of inflammatory factor of M1 phenotype TNF-α, IL-6 and IL-1β, and increasing TGF-β release and the mRNA levels of TGF-β and SOCS3, cytokine of M2 phenotype and its regulator. Moreover, the increased TNF-α induced by TOPK siRNA could be reversed by HDAC1/HDAC2 inhibitor, FK228. TOPK overexpression increased M2 marker expression in vivo concomitant with the amelioration of cerebral injury, neurological functions deficits, whereas TOPK silencing had the opposite effects, which were completely reversed by the FK228 and partially by the SAHA. These findings suggest that TOPK positively regulates microglia/macrophage M2 polarization by inhibiting HDAC1/HDAC2 activity, which may contribute to its neuroprotective effects against cerebral ischemia-reperfusion injury.

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Hyperglycemia Alters Astrocyte Metabolism and Inhibits Astrocyte Proliferation
Wenjun Li,Gourav Roy Choudhury,Ali Winters,Jude Prah,Wenping Lin,Ran Liu,Shao-Hua Yang
A&D    2018, 9 (4): 674-684.   DOI: 10.14336/AD.2017.1208
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Diabetes milieu is a complex metabolic disease that has been known to associate with high risk of various neurological disorders. Hyperglycemia in diabetes could dramatically increase neuronal glucose levels which leads to neuronal damage, a phenomenon referred to as glucose neurotoxicity. On the other hand, the impact of hyperglycemia on astrocytes has been less explored. Astrocytes play important roles in brain energy metabolism through neuron-astrocyte coupling. As the component of blood brain barrier, glucose might be primarily transported into astrocytes, hence, impose direct impact on astrocyte metabolism and function. In the present study, we determined the effect of high glucose on the energy metabolism and function of primary astrocytes. Hyperglycemia level glucose (25 mM) induced cell cycle arrest and inhibited proliferation and migration of primary astrocytes. Consistently, high glucose decreased cyclin D1 and D3 expression. High glucose enhanced glycolytic metabolism, increased ATP and glycogen content in primary astrocytes. In addition, high glucose activated AMP-activated protein kinase (AMPK) signaling pathway in astrocytes. In summary, our in vitro study indicated that hyperglycemia might impact astrocyte energy metabolism and function phenotype. Our study provides a potential mechanism which may underlie the diabetic cerebral neuropathy and warrant further in vivo study to determine the effect of hyperglycemia on astrocyte metabolism and function.

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Voxel-based Specific Regional Analysis System for Alzheimer’s Disease (VSRAD) on 3-tesla Normal Database: Diagnostic Accuracy in Two Independent Cohorts with Early Alzheimer’s Disease
Daichi Sone,Etsuko Imabayashi,Norihide Maikusa,Masayo Ogawa,Noriko Sato,Hiroshi Matsuda,Japanese-Alzheimer’s Disease Neuroimaging Initiative
A&D    2018, 9 (4): 755-760.   DOI: 10.14336/AD.2017.0818
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Voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD) software is widely used in clinical practice in Alzheimer’s disease (AD). The existing VSRAD is based on the normal database with 1.5-tesla MRI scans (VSRAD-1.5T), and its utility for patients have undergone 3-tesla MRI is still controversial. We recruited 19 patients with early AD and 28 healthy controls who had undergone 3-tesla MRI scans at our institute (Cohort 1). We also used the 3-tesla MRI data of 30 patients with early AD and 13 healthy controls from the Japanese Alzheimer’s Disease Neuroimaging Initiative (Cohort 2). We also created a new VSRAD based on 65 normal subjects’ 3-tesla MRI scans (VSRAD-3T), and compared the detectability of AD between VSRAD-1.5T and VSRAD-3T, using receiver operating characteristic curve and area under the curve (AUC) analyses. As a result, there were no significant differences in the detectability of AD between VSRAD-3T and VSRAD-1.5T, except for the whole white matter atrophy score, which showed significantly better AUC in VSRAD-3T than in VSRAD-1.5T in both Cohort 1 (p=0.04) and 2 (p<0.01). Generally, there were better diagnostic values in Cohort 2 than in Cohort 1. The optimal cutoff values varied but were generally lower than in the previously published data. In conclusion, for patients with 3-tesla MRI, the detectability of early AD by the existing VSRAD was not different from that by the new VSRAD based on 3-tesla database. We should exercise caution when using the existing VSRAD for 3-tesla white matter analyses or for setting cutoff values.

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Neuroprotective Effect of Caffeic Acid Phenethyl Ester in A Mouse Model of Alzheimer’s Disease Involves Nrf2/HO-1 Pathway
Fabiana Morroni,Giulia Sita,Agnese Graziosi,Eleonora Turrini,Carmela Fimognari,Andrea Tarozzi,Patrizia Hrelia
A&D    2018, 9 (4): 605-622.   DOI: 10.14336/AD.2017.0903
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Alzheimer’s disease (AD) is a progressive pathology, where dementia symptoms gradually worsen over a number of years. The hallmarks of AD, such as amyloid β-peptide (Aβ) in senile plaque and neurofibrillary tangles, are strongly intertwined with oxidative stress, which is considered one of the common effectors of the cascade of degenerative events. The endogenous nuclear factor erythroid 2-related factor 2 (Nrf2) is the "master regulator" of the antioxidant response and it is known as an indicator and regulator of oxidative stress. The present study aimed to determine the potential neuroprotective activity of caffeic acid phenethyl ester (CAPE), a polyphenolic compound abundant in honeybee, against the neurotoxicity of Aβ1-42 oligomers (AβO) in mice. An intracerebroventricular (i.c.v.) injection of AβO into the mouse brain triggered increased reactive oxygen species levels, neurodegeneration, neuroinflammation, and memory impairment. In contrast, the intraperitoneal administration of CAPE (10 mg/kg) after i.c.v. AβO-injection counteracted oxidative stress accompanied by an induction of Nrf2 and heme oxygenase-1 via the modulation of glycogen synthase kinase 3β in the hippocampus of mice. Additionally, CAPE treatment decreased AβO-induced neuronal apoptosis and neuroinflammation, and improved learning and memory, protecting mice against the decline in spatial cognition. Our findings demonstrate that CAPE could potentially be considered as a promising neuroprotective agent against progressive neurodegenerative diseases such as AD.

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Clinical Profile of Chinese Long-Term Parkinson’s Disease Survivors With 10 Years of Disease Duration and Beyond
Qian Sun,Tian Wang,Tian-Fang Jiang,Pei Huang,Ying Wang,Qin Xiao,Jun Liu,Sheng-Di Chen
A&D    2018, 9 (1): 8-16.   DOI: 10.14336/AD.2017.0204
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Background

Parkinson’s disease (PD) patients with 10 years or more survival (PD-10) are not well characterized. The aim of this study was to evaluate the main issues facing PD-10 patients and identify factors that independently contributed to quality of life (QoL).

Methods

A group of 121 PD-10 patients recruited from outpatient clinics participated in this cross-sectional study. Data on demographic and clinical factors were collected. Multiple linear regression analyses were conducted to identify determinants of poor QoL.

Results

The entire PD-10 patients had disease duration ranging from 10 to 23 years, with 84.2% of the total cohort skewed to between 10 and 15 years’ duration. The PD-10 patients had great frequency of left-sided onset, increased motor and non-motor symptoms as well as inferior QoL. The more advanced stage of disease in PD-10 patients was associated with motor phenotype, freezing of gait, higher UPDRS sub-scores and levodopa equivalent dose, less balanced confidence, fatigue, anxiety, depression, reduced quality of life and worse Timed Up & Go performance. Self-reported mood symptoms, decreased balance confidence and reduced daily activities were the three factors most closely associated with poorer QoL, but excessive daytime sleepiness and long disease duration additionally contributed to the explanatory power.

Conclusions

This is the first report to investigate the clinical characteristics of Chinese PD-10 patients. Our study may elucidate an important clue for understanding PD-10 patients in clinical practice and identifying patients with PD at risk for reduced QoL.

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The Role of Pulmonary and Systemic Immunosenescence in Acute Lung Injury
Christina Brandenberger,Katharina Maria Kling,Marius Vital,Mühlfeld Christian
A&D    2018, 9 (4): 553-565.   DOI: 10.14336/AD.2017.0902
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Acute lung injury (ALI) is associated with increased morbidity and mortality in the elderly (> 65 years), but the knowledge about origin and effects of immunosenescence in ALI is limited. Here, we investigated the immune response at pulmonary, systemic and cellular level in young (2-3 months) and old (18-19 months) C57BL/6J mice to localize and characterize effects of immunosenescence in ALI. ALI was induced by intranasal lipopolysaccharide (LPS) application and the animals were sacrificed 24 or 72 h later. Pulmonary inflammation was investigated by analyzing histopathology, bronchoalveolar lavage fluid (BALF) cytometry and cytokine expression. Systemic serum cytokine expression, spleen lymphocyte populations and the gut microbiome were analyzed, as well as activation of alveolar and bone marrow derived macrophages (BMDM) in vitro. Pulmonary pathology of ALI was more severe in old compared with young mice. Old mice showed significantly more inflammatory cells and pro-inflammatory cyto- or chemokines (TNFα, IL-6, MCP-1, CXCL1, MIP-1α) in the BALF, but a delayed expression of cytokines associated with activation of adaptive immunity and microbial elimination (IL-12 and IFNγ). Alveolar macrophages, but not BMDM, of old mice showed greater activation after in vivo and in vitro stimulation with LPS. No systemic enhanced pro-inflammatory cytokine response was detected in old animals after LPS exposure, but a delayed expression of IL-12 and IFNγ. Furthermore, old mice had less CD8+ T-cells and NK cells and more regulatory T-cells in the spleen compared with young mice and a distinct gut microbiome structure. The results of our study show an increased alveolar macrophage activation and pro-inflammatory signaling in the lungs, but not systemically, suggesting a key role of senescent alveolar macrophages in ALI. A decrease in stimulators of adaptive immunity with advancing age might further promote the susceptibility to a worse prognosis in ALI in elderly.

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Diagnostic and Immunosuppressive Potential of Elevated Mir-424 Levels in Circulating Immune Cells of Ischemic Stroke Patients
Guangwen Li,Qingfeng Ma,Rongliang Wang,Zhibin Fan,Zhen Tao,Ping Liu,Haiping Zhao,Yumin Luo
A&D    2018, 9 (2): 172-781.   DOI: 10.14336/AD.2017.0602
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Our previous study demonstrated that microRNA-424 (miR-424) protected against experimental stroke through inhibition of microglial proliferation and activation by targeting cell cycle proteins. The purpose of this study was to further explore the clinical significance of miR-424 in peripheral immune cells of patients with acute ischemic stroke (AIS). Blood samples were collected from 40 patients within 6 hours of symptom onset and 27 control subjects. MiR-424 levels in lymphocytes, neutrophils and plasma were determined by quantitative realtime-PCR. The diagnostic sensitivity and specificity of miR-424 for stroke was evaluated by receiver operator characteristic (ROC) curve. The correlation between miR-424 levels and clinical data was analyzed using Pearson’s correlation test. Plasma levels of inflammatory mediators (TNF-α, IL-10) and neurotrophic factor (IGF-1) were detected by ELISA. Notably, miR-424 expression levels in lymphocytes and neutrophils increased after stroke, suggestive of its diagnostic value in ischemic stroke. MiR-424 levels in neutrophils were negatively correlated with infarct volume. Lymphocytic miR-424 levels were negatively correlated with the number of lymphocytes and the expression of cyclin-dependent kinase CDK6. Moreover, plasma TNF-α and IGF-1 levels increased and decreased, respectively, in stroke patients, and miR-424 levels in lymphocytes and neutrophils were both inversely correlated with plasma TNF-α, IL-10, or IGF-1 levels. In summary, miR-424 levels in peripheral immune cells has diagnostic potential for ischemic stroke, and might affect the severity of acute stroke by depressing the peripheral inflammatory response through CDK6-dependent pathway in lymphocytes or CDK6-independent pathway neutrophils.

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Apelin Ameliorates High Glucose-Induced Downregulation of Connexin 43 via AMPK-Dependent Pathway in Neonatal Rat Cardiomyocytes
Xiaoting Li,Lu Yu,Jing Gao,Xukun Bi,Juhong Zhang,Shiming Xu,Meihui Wang,Mengmeng Chen,Fuyu Qiu,Guosheng Fu
A&D    2018, 9 (1): 66-76.   DOI: 10.14336/AD.2017.0426
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Diabetes Mellitus is a common disorder, with increasing risk of cardiac arrhythmias. Studies have shown that altered connexin expression and gap junction remodeling under hyperglycemia contribute to the high prevalence of cardiac arrhythmias and even sudden death. Connexin 43 (Cx43), a major protein that assembles to form cardiac gap junctions, has been found to be downregulated under high glucose conditions, along with inhibition of gap junctional intercellular communication (GJIC). While, apelin, a beneficial adipokine, increases Cx43 protein expression in mouse and human embryonic stem cells during cardiac differentiation. However, it remains unknown whether apelin influences GJIC capacity in cardiomyocytes. Here, using Western blotting and dye transfer assays, we found that Cx43 protein expression was reduced and GJIC was impaired after treatment with high glucose, which, however, could be abrogated after apelin treatment for 48 h. We also found that apelin increased Cx43 expression under normal glucose. Real-time PCR showed that the Cx43 mRNA was not significantly affected under high glucose conditions in the presence of apelin or high glucose and apelin. High glucose decreased the phosphorylation of AMPKα; however, apelin activated AMPKα. Interestingly, we found that Cx43 expression was increased after treatment with AICAR, an activator of AMPK signaling. AMPKα inhibition mediated with transfection of siRNA-AMPKα1 and siRNA-AMPKα2 abolished the protective effect of apelin on Cx43 expression. Our data suggest that apelin attenuates high glucose-induced Cx43 downregulation and improves the loss of functional gap junctions partly through the AMPK pathway.

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Mitochondria in Ischemic Stroke: New Insight and Implications
Fan Liu, Jianfei Lu, Anatol Manaenko, Junjia Tang, Qin Hu
Aging and disease    2018, 9 (5): 924-937.   DOI: 10.14336/AD.2017.1126
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Stroke is the leading cause of death and adult disability worldwide. Mitochondrial dysfunction has been regarded as one of the hallmarks of ischemia/reperfusion (I/R) induced neuronal death. Maintaining the function of mitochondria is crucial in promoting neuron survival and neurological improvement. In this article, we review current progress regarding the roles of mitochondria in the pathological process of cerebral I/R injury. In particular, we emphasize on the most critical mechanisms responsible for mitochondrial quality control, as well as the recent findings on mitochondrial transfer in acute stroke. We highlight the potential of mitochondria as therapeutic targets for stroke treatment and provide valuable insights for clinical strategies.

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Exploration of Novel Anti-Oxidant Protein Sestrin in Frailty Syndrome in Elderly
Nitish Rai,G. Venugopalan,Rashmita Pradhan,Akash Ambastha,Ashish Datt Upadhyay,Sadanand Dwivedi,Aparajit B. Dey,Sharmistha Dey
A&D    2018, 9 (2): 220-227.   DOI: 10.14336/AD.2017.0423
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Frailty in elderly is very much familiar with a decline in the musculoskeletal system. Muscle degeneration in the lower organism was observed due to loss of anti-oxidant protein Sestrin. The aim of the study is to determine the level of Sestrin1 and Sestrin2 in the serum of frail and non-frail elderly to associate their impact in frailty syndrome. Subjects with age ≥ 65 years were enrolled from Geriatric Medicine OPD of All India Institute of Medical Sciences, New Delhi (N= 92). Among them, 51 subjects were identified as frail and rest 41 were regarded as non-frail according to “deficit accumulation model of Rockwood.” The study was performed by surface plasmon resonance and validated by western blot. Sestrin1 and Sestrin2 were found to be significantly reduced in frail compare to non-frail elderly. Furthermore, even after the adjustment for age, gender and education, the level of Sestrin1 and Sestrin2 remain significantly lower across the groups. The Sestrin1 level was significantly lower in various categories like age, gender, BMI, education, ADL, number of co-morbidity along with other clinico-pathological features. ROC analysis also revealed the distinction of frail and non-frail in respect to serum Sestrin1 and Sestrin2. This study highlighted the new and promising role of serum Sestrin in frail and non-frail elderly. In future, it can be utilized as molecular marker to assess the potential diagnostic value for clinical purpose.

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Urinary Neutrophil Gelatinase-Associated Lipocalin Is Excellent Predictor of Acute Kidney Injury in Septic Elderly Patients
Erica Pires da Rocha,Lais Gabriela Yokota,Beatriz Motta Sampaio,Karina Zanchetta Cardoso Eid,Dayana Bitencourt Dias,Fernanda Moreira de Freitas,Andre Luis Balbi,Daniela Ponce
A&D    2018, 9 (2): 182-191.   DOI: 10.14336/AD.2017.0307
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Elderly is the main age group affected by acute kidney injury (AKI). There are no studies that investigated the predictive properties of urinary (u) NGAL as an AKI marker in septic elderly population. This study aimed to evaluate the efficacy of uNGAL as predictor of AKI diagnosis and prognosis in elderly septic patients admitted to ICUs. We prospectively studied elderly patients with sepsis admitted to ICUs from October 2014 to November 2015. Assessment of renal function was performed daily by serum creatinine and urine output. The level of uNGAL was performed within the first 48 hours of the diagnosis of sepsis (NGAL1) and between 48 and 96 hours (NGAL2). The results were presented using descriptive statistics and area under the receiver operating characteristic curve (AUC-ROC) and p value was 5%. Seventy-five patients were included, 47 (62.7%) developed AKI. At logistic regression, chronic kidney disease and low mean blood pressure at admission were identified as factors associated with AKI (OR=0.05, CI=0.01-0.60, p=0.045 and OR=0.81, CI=0,13-0.47; p=0.047). The uNGAL was excellent predictor of AKI diagnosis (AUC-ROC >0.95, and sensitivity and specificity>0.89), anticipating the AKI diagnosis in 2.1±0.3 days. Factors associated with mortality in the logistic regression were presence of AKI (OR=2.14, CI=1.42-3.98, p=0.04), chronic obstructive pulmonary disease (OR = 9.37, CI =1.79-49.1, p=0.008) and vasoactive drugs (OR=2.06, CI=0.98-1.02, p=0.04). The accuracy of NGALu 1 and 2 as predictors of death was intermediate, with AUC-ROC of 0.61 and 0.62; sensitivity between 0.65 and 0.77 and specificity lower than 0.6. The uNGAL was excellent predictor of AKI in septic elderly patients in ICUs and can anticipate the diagnosis of AKI in 2.1 days.

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Fucoidan Protects Dopaminergic Neurons by Enhancing the Mitochondrial Function in a Rotenone-induced Rat Model of Parkinson’s Disease
Li Zhang,Junwei Hao,Yan Zheng,Ruijun Su,Yajin Liao,Xiaoli Gong,Limin Liu,Xiaomin Wang
A&D    2018, 9 (4): 590-604.   DOI: 10.14336/AD.2017.0831
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The mitochondrion is susceptible to neurodegenerative disorders such as Parkinson’s disease (PD). Mitochondrial dysfunction has been considered to play an important role in the dopaminergic degeneration in PD. However, there are no effective drugs to protect mitochondria from dysfunction during the disease development. In the present study, fucoidan, a sulfated polysaccharide derived from Laminaria japonica, was investigated and characterized for its protective effect on the dopamine system and mitochondrial function of dopaminergic neurons in a rotenone-induced rat model of PD. We found that chronic treatment with fucoidan significantly reversed the loss of nigral dopaminergic neurons and striatal dopaminergic fibers and the reduction of striatal dopamine levels in PD rats. Fucoidan also alleviated rotenone-induced behavioral deficits. Moreover, the mitochondrial respiratory function as detected by the mitochondrial oxygen consumption and the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and nuclear transcription factor 2 (NRF2) were reduced in the substantia nigra of PD rats, which were markedly reversed by fucoidan. Oxidative products induced by rotenone were significantly reduced by fucoidan. Taken together, these results demonstrate that fucoidan possesses the ability to protect the dopamine system in PD rats. The neuroprotective effect of fucoidan may be mediated via reserving mitochondrial function involving the PGC-1α/NRF2 pathway. This study provides new evidence that fucoidan can be explored in PD therapy.

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Superoxide Radical Dismutation as New Therapeutic Strategy in Parkinson’s Disease
Federica De Lazzari,Luigi Bubacco,Alexander J Whitworth,Marco Bisaglia
A&D    2018, 9 (4): 716-728.   DOI: 10.14336/AD.2017.1018
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Aging is the biggest risk factor for developing many neurodegenerative disorders, including idiopathic Parkinson’s disease (PD). PD is still an incurable disorder and the available medications are mainly directed to the treatment of symptoms in order to improve the quality of life. Oxidative injury has been identified as one of the principal factors involved in the progression of PD and several indications are now reported in the literature highlighting the prominent role of the superoxide radical in inducing neuronal toxicity. It follows that superoxide anions represent potential cellular targets for new drugs offering a novel therapeutic approach to cope with the progression of the disease. In this review we first present a comprehensive overview of the most common cellular reactive oxygen and nitrogen species, describing their cellular sources, their potential physiological roles in cell signalling pathways and the mechanisms through which they could contribute to the oxidative damage. We then analyse the potential therapeutic use of SOD-mimetic molecules, which can selectively remove superoxide radicals in a catalytic way, focusing on the classes of molecules that have therapeutically exploitable properties.

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Gait Analyses in Mice: Effects of Age and Glutathione Deficiency
J. Thomas Mock,Sherilynn G Knight,Philip H Vann,Jessica M Wong,Delaney L Davis,Michael J Forster,Nathalie Sumien
A&D    2018, 9 (4): 634-646.   DOI: 10.14336/AD.2017.0925
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Minor changes (~0.1 m/s) in human gait speed are predictive of various measures of decline and can be used to identify at-risk individuals prior to further decline. These associations are possible due to an abundance of human clinical research. However, age-related gait changes are not well defined in rodents, even though rodents are used as the primary pre-clinical model for many disease states as well as aging research. Our study investigated the usefulness of a novel automated system, the CatWalk™ XT, to measure age-related differences in gait. Furthermore, age-related functional declines have been associated with decreases in the reduced to oxidized glutathione ratio leading to a pro-oxidizing cellular shift. Therefore the secondary aim of this study was to determine whether chronic glutathione deficiency led to exacerbated age-associated impairments. Groups of male and female wild-type (gclm+/+) and knock-out (gclm-/-) mice aged 4, 10 and 17 months were tested on the CatWalk and gait measurements recorded. Similar age-related declines in all measures of gait were observed in both males and females, and chronic glutathione depletion was associated with some delays in age-related declines, which were further exacerbated. In conclusion, the CatWalk is a useful tool to assess gait changes with age, and further studies will be required to identify the potential compensating mechanisms underlying the effects observed with the chronic glutathione depletion.

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Pkcδ Activation is Involved in ROS-Mediated Mitochondrial Dysfunction and Apoptosis in Cardiomyocytes Exposed to Advanced Glycation End Products (Ages)
Yao-Chih Yang,Cheng-Yen Tsai,Chien-Lin Chen,Chia-Hua Kuo,Chien-Wen Hou,Shi-Yann Cheng,Ritu Aneja,Chih-Yang Huang,Wei-Wen Kuo
A&D    2018, 9 (4): 647-663.   DOI: 10.14336/AD.2017.0924
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Diabetic patients exhibit serum AGE accumulation, which is associated with reactive oxygen species (ROS) production and diabetic cardiomyopathy. ROS-induced PKCδ activation is linked to mitochondrial dysfunction in human cells. However, the role of PKCδ in cardiac and mitochondrial dysfunction caused by AGE in diabetes is still unclear. AGE-BSA-treated cardiac cells showed dose- and time-dependent cell apoptosis, ROS generation, and selective PKCδ activation, which were reversed by NAC and rotenone. Similar tendency was also observed in diabetic and obese animal hearts. Furthermore, enhanced apoptosis and reduced survival signaling by AGE-BSA or PKCδ-WT transfection were reversed by kinase-deficient (KD) of PKCδ transfection or PKCδ inhibitor, respectively, indicating that AGE-BSA-induced cardiomyocyte death is PKCδ-dependent. Increased levels of mitochondrial mass as well as mitochondrial fission by AGE-BSA or PKCδ activator were reduced by rottlerin, siPKCδ or KD transfection, indicating that the AGE-BSA-induced mitochondrial damage is PKCδ-dependent. Using super-resolution microscopy, we confirmed that PKCδ colocalized with mitochondria. Interestingly, the mitochondrial functional analysis by Seahorse XF-24 flux analyzer showed similar results. Our findings indicated that cardiac PKCδ activation mediates AGE-BSA-induced cardiomyocyte apoptosis via ROS production and may play a key role in the development of cardiac mitochondrial dysfunction in rats with diabetes and obesity.

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Glucocerebrosidase mRNA is Diminished in Brain of Lewy Body Diseases and Changes with Disease Progression in Blood
Laia Perez-Roca,Cristina Adame-Castillo,Jaume Campdelacreu,Lourdes Ispierto,Dolores Vilas,Ramon Rene,Ramiro Alvarez,Jordi Gascon-Bayarri,Maria A. Serrano-Munoz,Aurelio Ariza,Katrin Beyer
A&D    2018, 9 (2): 208-219.   DOI: 10.14336/AD.2017.0505
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Parkinson disease (PD) and dementia with Lewy bodies (DLB) are Lewy body diseases characterized by abnormal alpha-synuclein deposits and overlapping pathological features in the brain. Several studies have shown that glucocerebrosidase (GBA) deficiency is involved in the development of LB diseases. Here, we aimed to find out if this deficiency starts at the transcriptional level, also involves alternative splicing, and if GBA expression changes in brain are also detectable in blood of patients with LB diseases. The expression of three GBA transcript variants (GBAtv1, GBAtv2 and GBAtv5) was analyzed in samples from 20 DLB, 25 PD and 17 control brains and in blood of 20 DLB, 26 PD patients and 17 unaffected individuals. Relative mRNA expression was determined by real-time PCR. Expression changes were evaluated by the ΔΔCt method. In brain, specific expression profiles were identified in the temporal cortex of DLB and in the caudate nucleus of PD. In blood, significant GBA mRNA diminution was found in both DLB and PD patients. Early PD and early-onset DLB patients showed lowest GBA levels which were normal in PD patients with advanced disease and DLB patients who developed disease after 70 years of age. In conclusion, disease group specific GBA expression profiles were found in mostly affected areas of LBD. In blood, GBA expression was diminished in LB diseases, especially in patients with early onset DLB and in patients with early PD. Age of disease onset exerts an opposite effect on GBA expression in DLB and PD.

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MicroRNAs and Presbycusis
Weiming Hu,Junwu Wu,Wenjing Jiang,Jianguo Tang
A&D    2018, 9 (1): 133-142.   DOI: 10.14336/AD.2017.0119
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Presbycusis (age-related hearing loss) is the most universal sensory degenerative disease in elderly people caused by the degeneration of cochlear cells. Non-coding microRNAs (miRNAs) play a fundamental role in gene regulation in almost every multicellular organism, and control the aging processes. It has been identified that various miRNAs are up- or down-regulated during mammalian aging processes in tissue-specific manners. Most miRNAs bind to specific sites on their target messenger-RNAs (mRNAs) and decrease their expression. Germline mutation may lead to dysregulation of potential miRNAs expression, causing progressive hair cell degeneration and age-related hearing loss. Therapeutic innovations could emerge from a better understanding of diverse function of miRNAs in presbycusis. This review summarizes the relationship between miRNAs and presbycusis, and presents novel miRNAs-targeted strategies against presbycusis.

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Brain Interstitial Fluid Drainage Alterations in Glioma-Bearing Rats
Xiangping Guan,Wei Wang,Aibo Wang,Ze Teng,Hongbin Han
A&D    2018, 9 (2): 228-234.   DOI: 10.14336/AD.2017.0415
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Real time imaging and measurement of the drug distribution in the brain interstitial space (ISS) are able to determine the effeicency of local brain drug delivery to treatment gliomas. In the present study, we used a tracer-based magnetic resonance imaging (MRI) method to quantitatively analyze the effects of glioma growth on ISF drainage. Sprague-Dawley rats were randomly divided into six groups (n = 6). C6 glioma cells were implanted into either the caudate nucleus or thalamus of rats and then were examined 10 or 20 days after implantation. The two control groups were treated with vehicle. A tracer was injected into the caudate nucleus of control rats and rats with gliomas growing in the thalamus for 10 or 20 days. The tracer was similarly injected into the thalamus of control rats and rats implanted with gliomas in the caudate nucleus. The diffusion and clearance parameters of the tracer were calculated using tracer-based MRI techniques. We found that glioma implanted in the caudate nucleus significantly decreased the speed of the ISF flow in thalamus. With the growth of the glioma in thalamus, the drainage route of the brain ISF flow was altered in the caudate nucleus, but the speed of the flow was not significantly changed. These findings indicate that tracer-based MRI is a promising technique for optimizing the interstitial administration of therapeutics aimed at treating brain gliomas.

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Trefoil Factor 3, Cholinesterase and Homocysteine: Potential Predictors for Parkinson’s Disease Dementia and Vascular Parkinsonism Dementia in Advanced Stage
Jing Zou,Zhigang Chen,Caiqian Liang,Yongmei Fu,Xiaobo Wei,Jianjun Lu,Mengqiu Pan,Yue Guo,Xinxue Liao,Huifang Xie,Duobin Wu,Min Li,Lihui Liang,Penghua Wang,Qing Wang
A&D    2018, 9 (1): 51-65.   DOI: 10.14336/AD.2017.0416
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Trefoil factor 3 (TFF3), cholinesterase activity (ChE activity) and homocysteine (Hcy) play critical roles in modulating recognition, learning and memory in neurodegenerative diseases, such as Parkinson’s disease dementia (PDD) and vascular parkinsonism with dementia (VPD). However, whether they can be used as reliable predictors to evaluate the severity and progression of PDD and VPD remains largely unknown. Methods: We performed a cross-sectional study that included 92 patients with PDD, 82 patients with VPD and 80 healthy controls. Serum levels of TFF3, ChE activity and Hcy were measured. Several scales were used to rate the severity of PDD and VPD. Receivers operating characteristic (ROC) curves were applied to map the diagnostic accuracy of PDD and VPD patients compared to healthy subjects. Results: Compared with healthy subjects, the serum levels of TFF3 and ChE activity were lower, while Hcy was higher in the PDD and VPD patients. These findings were especially prominent in male patients. The three biomarkers displayed differences between PDD and VPD sub-groups based on genders and UPDRS (III) scores’ distribution. Interestingly, these increased serum Hcy levels were significantly and inversely correlated with decreased TFF3/ChE activity levels. There were significant correlations between TFF3/ChE activity/Hcy levels and PDD/VPD severities, including motor dysfunction, declining cognition and mood/gastrointestinal symptoms. Additionally, ROC curves for the combination of TFF3, ChE activity and Hcy showed potential diagnostic value in discriminating PDD and VPD patients from healthy controls. Conclusions: Our findings suggest that serum TFF3, ChE activity and Hcy levels may underlie the pathophysiological mechanisms of PDD and VPD. As the race to find biomarkers or predictors for these diseases intensifies, a better understanding of the roles of TFF3, ChE activity and Hcy may yield insights into the pathogenesis of PDD and VPD.

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Pro- and Anti-inflammatory Effects of High Cholesterol Diet on Aged Brain
Yali Chen, Mengmei Yin, Xuejin Cao, Gang Hu, Ming Xiao
Aging and disease    2018, 9 (3): 374-390.   DOI: 10.14336/AD.2017.0706
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Both hypercholesterolemia and aging are related to cognitive decline or Alzheimer’s disease. However, their interactive influence on the neurodegenerative progress remains unclear. To address this issue, 6-month-old and 16-month-old female mice were fed a 3% cholesterol diet for 8 weeks, followed by hippocampus-related functional, pathological, biochemical and molecular analyses. The high cholesterol diet did not exacerbate age-dependent cognitive decline and hippocampal neuronal death, and even greatly mitigated decreases of synaptophysin and growth associated protein 43 expression in the hippocampus of aged mice. Compared with young controls, aged mice fed normal diet showed mild activation of hippocampal microglia with increased expression of CD68, a marker of the microglial M1 phenotype, and decreased expression of CD206, a marker of the microglial M2 phenotype. More interestingly, the high cholesterol diet not only improved NLRP3 inflammasome activation and IL-1β expression, but also increased levels of anti-inflammatory cytokines IL-4 and IL-6 in the hippocampus of old mice, suggesting playing pro- and anti-neuroinflammatory effects. In addition, the cholesterol rich diet resulted in a defect of the blood-brain barrier of aged hippocampus, as revealed by increased brain albumin content. These results have revealed both harmful and protective effects of high cholesterol diet on aged brain, which helps us to understand that hypercholesterolemia in the aged population is not associated with dementia and cognitive impairment.

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N-acetylcysteine Treatment Reduces Age-related Hearing Loss and Memory Impairment in the Senescence-Accelerated Prone 8 (SAMP8) Mouse Model
Aurore Marie,Johann Meunier,Emilie Brun,Susanna Malmstrom,Veronique Baudoux,Elodie Flaszka,Gaëlle Naert,François Roman,Sylvie Cosnier-Pucheu,Sergio Gonzalez-Gonzalez
A&D    2018, 9 (4): 664-673.   DOI: 10.14336/AD.2017.0930
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Age-related hearing loss (ARHL) is the most common sensory disorder in the elderly population. SAMP8 mouse model presents accelerated senescence and has been identified as a model of gerontological research. SAMP8 displays a progressive age-related decline in brain function associated with a progressive hearing loss mimicking human aging memory deficits and ARHL. The molecular mechanisms associated with SAMP8 senescence process involve oxidative stress leading to chronic inflammation and apoptosis. Here, we studied the effect of N-acetylcysteine (NAC), an antioxidant, on SAMP8 hearing loss and memory to determine the potential interest of this model in the study of new antioxidant therapies. We observed a strong decrease of auditory brainstem response thresholds from 45 to 75 days of age and an increase of distortion product amplitudes from 60 to 75 days in NAC treated group compared to vehicle. Moreover, NAC treated group presented also an increase of memory performance at 60 and 105 days of age. These results confirm that NAC delays the senescence process by slowing the age-related hearing loss, protecting the cochlear hair cells and improving memory, suggesting that antioxidants could be a pharmacological target for age-related hearing and memory loss.

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Chronic Remote Ischemic Conditioning May Mimic Regular Exercise:Perspective from Clinical Studies
Wenbo Zhao,Sijie Li,Changhong Ren,Ran Meng,Xunming Ji
A&D    2018, 9 (1): 165-171.   DOI: 10.14336/AD.2017.1015
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Chronic remote ischemic conditioning (RIC), particularly long-term repeated RIC, has been applied in clinical trials with the expectation that it could play its protective roles for protracted periods. In sports medicine, chronic RIC has also been demonstrated to improve exercise performance, akin to improvements seen with regular exercise training. Therefore, chronic RIC may mimic regular exercise, and they may have similar underlying mechanisms. In this study, we explored the common underlying mechanisms of chronic RIC and physical exercise in protecting multiple organs and benefiting various populations, the advantages of chronic RIC, and the challenges for its popularization. Intriguingly, several underlying mechanisms of RIC and exercise have been shown to overlap. These include the production of many autacoids, enhanced ability for antioxidant activity, modulating immune and inflammatory responses. Therefore, it appears that chronic RIC, just like regular exercise, has beneficial effects in unhealthy, sub-healthy and healthy individuals. Compared with regular exercise, chronic RIC has several advantages, which may provide novel insights into the area of exercise and health. Chronic RIC may enrich the modes of exercise, and benefit individuals with severe diseases. Also, the disabled, and sub-healthy individuals are likely to benefit from chronic RIC either as an alternative to exercise or an adjunct to pharmacological or non-pharmacological therapy.

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The Effect of Aquaporin-4 Knockout on Interstitial Fluid Flow and the Structure of the Extracellular Space in the Deep Brain
Ze Teng, Aibo Wang, Peng Wang, Rui Wang, Wei Wang, Hongbin Han
Aging and disease    2018, 9 (5): 808-816.   DOI: 10.14336/AD.2017.1115
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It has been reported that aquaporin-4 (AQP4) deficiency impairs transportation between the cerebrospinal fluid and interstitial fluid (ISF) as well as the clearance of interstitial solutes in the superficial brain. However, the effect of AQP4 on ISF flow in the deep brain remains unclear. This study compared the brain ISF flow in the caudate nucleus and thalamus of normal rats (NO) and AQP4 knockout rats (KO) using tracer-based magnetic resonance imaging. The rate of brain ISF flow slowed to different degrees in the two regions of KO rats’ brains. Compared with NO rats, the half-life of ISF in the thalamus of KO rats was significantly prolonged, with a corresponding decrease in the clearance coefficient. The tortuosity of the brain extracellular space (ECS) was unchanged in the thalamus of KO rats. In the caudate nucleus of KO rats, the volume fraction of the ECS and the diffusion coefficient were increased, with significantly decreased tortuosity; no significant changes in brain ISF flow were demonstrated. Combined with a change in the expression of glial fibrillary acidic protein and AQP4 in two brain regions, we found that the effect of AQP4 knockout on ISF flow and ECS structure in these two regions differed. This difference may be related to the distribution of astrocytes and the extent of AQP4 decline. This study provides evidence for the involvement of AQP4 in ISF transportation in the deep brain and provides a basis for the establishment of a pharmacokinetic model of the brain’s interstitial pathway.

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Alteration of Copper Fluxes in Brain Aging: A Longitudinal Study in Rodent Using 64CuCl2-PET/CT
Fangyu Peng,Fang Xie,Otto Muzik
A&D    2018, 9 (1): 109-118.   DOI: 10.14336/AD.2017.1025
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Brain aging is associated with changes of various metabolic pathways. Copper is required for brain development and function, but little is known about changes in copper metabolism during brain aging. The objective of this study was to investigate alteration of copper fluxes in the aging mouse brain with positron emission tomography/computed tomography using 64CuCl2 as a radiotracer (64CuCl2-PET/CT). A longitudinal study was conducted in C57BL/6 mice (n = 5) to measure age-dependent brain and whole-body changes of 64Cu radioactivity using PET/CT after oral administration of 64CuCl2 as a radiotracer. Cerebral 64Cu uptake at 13 months of age (0.17 ± 0.05 %ID/g) was higher than the cerebral 64Cu uptake at 5 months of age (0.11 ± 0.06 %ID/g, p < 0.001), followed by decrease to (0.14 ± 0.04 %ID/g, p = 0.02) at 26 months of age. In contrast, cerebral 18F-FDG uptake was highest at 5 months of age (7.8 ± 1.2 %ID/g) and decreased to similar values at 12 (5.2 ± 1.1 %ID/g, p < 0.001) and 22 (5.6 ± 1.1 %ID/g, p < 0.001) months of age. The findings demonstrated alteration of copper fluxes associated with brain aging and the time course of brain changes in copper fluxes differed from changes in brain glucose metabolism across time, suggesting independent underlying physiological processes. Hence, age-dependent changes of cerebral copper fluxes might represent a novel metabolic biomarker for assessment of human brain aging process with PET/CT using 64CuCl2 as a radiotracer.

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