RESUMO
Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.
Assuntos
Apolipoproteínas E , Demência Frontotemporal , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas tau , Humanos , Demência Frontotemporal/genética , Proteínas tau/genética , Apolipoproteínas E/genética , Masculino , Feminino , Idoso , Polimorfismo de Nucleotídeo Único , Loci Gênicos , Pessoa de Meia-Idade , Estudos de Casos e Controles , Proteínas da MielinaRESUMO
The role of tumor necrosis factor-α (TNF-α) in Alzheimer's disease (AD) has recently become a topic of debate. TNF-α levels increase in the blood of patients with AD, and amyloid beta (Aß) plaques contain TNF-α deposits. The therapeutic efficacy of blocking TNF-α in patients with AD remains controversial as it is mostly based on preclinical studies. Thus, whether and how TNF-α contributes to amyloidogenic processes in AD is still an open question to be addressed. We analyzed plasma TNF-α and Aß42 levels in patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and AD, and in healthy volunteers (HLT). In addition, we performed correlation analysis to evaluate whether changes in plasma TNF-α levels correlate with cognitive decline, Aß42 levels, age, and BMI, which are all factors considered to contribute to or predispose individuals to AD. We found that TNF-α and Aß42 plasma levels were higher in patients with AD than in HLT individuals. High TNF-α levels were also observed in patients with SCI, in whom TNF-α and Aß42 levels were negatively correlated. Notably, TNF-α did not affect the amyloidogenic pathway in human microglial cultures exposed to 48 h of incubation, although it did trigger neuroinflammatory processes. These results imply that high TNF-α levels are more likely to be a clinical condition linked to AD than are direct contributors. Nonetheless, elevated levels of TNF-α in early-stage patients, like those with SCI and MCI, may provide a distinguishing feature for identifying clinical profiles that are at risk of having a poorer outcome in AD and could benefit from tailored therapies.
RESUMO
Recently, measurable peripheral biomarkers in the plasma of patients with Alzheimer's disease (AD) have gained considerable clinical interest. Several studies have identified one or more blood signatures that may facilitate the development of novel diagnostic and therapeutic strategies. For instance, changes in peripheral amyloid ß42 (Aß42) levels have been largely investigated in patients with AD and correlated with the progression of the pathology, although with controversial results. In addition, tumor necrosis factor α (TNFα) has been identified as an inflammatory biomarker strongly associated with AD, and several studies have consistently suggested the pharmacological targeting of TNFα to reduce systemic inflammation and prevent neurotoxicity in AD. Moreover, alterations in plasma metabolite levels appear to predict the progression of systemic processes relevant to brain functions. In this study, we analyzed the changes in the levels of Aß42, TNFα, and plasma metabolites in subjects with AD and compared the results with those in healthy elderly (HE) subjects. Differences in plasma metabolites of patients with AD were analyzed with respect to Aß42, TNFα, and the Mini-Mental State Examination (MMSE) score, searching for plasma signatures that changed simultaneously. In addition, the phosphorylation levels of the Tyr682 residue of the amyloid precursor protein (APP), which we previously proposed as a biomarker of AD, were measured in five HE and five AD patients, in whom the levels of Aß42, TNFα, and two plasma lipid metabolites increased simultaneously. Overall, this study highlights the potential of combining different plasma signatures to define specific clinical phenotypes of patient subgroups, thus paving the way for the stratification of patients with AD and development of personalized approaches.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , Fator de Necrose Tumoral alfa , Biomarcadores , Precursor de Proteína beta-Amiloide , Fragmentos de Peptídeos , Proteínas tauRESUMO
BACKGROUND: Although physical activity (PA) has been shown to enhance hypertension control, the impact of exercise on the potential decrease of the use of antihypertensive medications remains inadequately researched. AIM: The aim was to assess the impact of a two-year PA on the medication requirements of individuals with hypertension. METHODS: A clinical trial was conducted, involving 130 participants with essential hypertension who took at least one antihypertensive medication. Participants were randomly assigned to either a control group (CG n = 65) or an experimental group (EG n = 65) that underwent a 24-month supervised PA program based on a combination of aerobic and resistance training. The antihypertensive drug load for each participant was determined by adding the ratios of the prescribed daily dose (PDD) to the defined daily dose (DDD) for all antihypertensive medications taken by the participants. The outcome measures were evaluated at 0, 6, 12, 18, and 24 months. RESULTS: A total of 76 participants completed the 24-month assessment, and RM-ANOVA revealed a significantly lower antihypertensive drug load in the EG compared to the CG at 18 (p < 0.017) and 24 months (p < 0.003). CONCLUSION: A long-term PA program can decrease the antihypertensive drug load in older adults with essential hypertension. The trend of improvement regarding the EG drug load intake and the trend of CG drug load increase, although not significant over time, results in a significant difference between the groups at 18 months and an even greater difference at 24 months. This trend certifies the protective value of PA against the aging process and its related health risk factors.
RESUMO
Alzheimer's disease (AD), a neurodegenerative disorder, is the most common cause of dementia in the elderly population. Since its original description, there has been intense debate regarding the factors that trigger its pathology. It is becoming apparent that AD is more than a brain disease and harms the whole-body metabolism. We analyzed 630 polar and apolar metabolites in the blood of 20 patients with AD and 20 healthy individuals, to determine whether the composition of plasma metabolites could offer additional indicators to evaluate any alterations in the metabolic pathways related to the illness. Multivariate statistical analysis showed that there were at least 25 significantly dysregulated metabolites in patients with AD compared with the controls. Two membrane lipid components, glycerophospholipids and ceramide, were upregulated, whereas glutamic acid, other phospholipids, and sphingolipids were downregulated. The data were analyzed using metabolite set enrichment analysis and pathway analysis using the KEGG library. The results showed that at least five pathways involved in the metabolism of polar compounds were dysregulated in patients with AD. Conversely, the lipid pathways did not show significant alterations. These results support the possibility of using metabolome analysis to understand alterations in the metabolic pathways related to AD pathophysiology.
Assuntos
Doença de Alzheimer , Humanos , Idoso , Doença de Alzheimer/metabolismo , Metabolômica/métodos , Metaboloma/fisiologia , Espectrometria de Massas , Redes e Vias MetabólicasRESUMO
BACKGROUND: Parkinson's Disease (PD) is the second most frequent degenerative disorder, the risk of which increases with age. A preclinical PD diagnostic test does not exist. We identify PD blood metabolites and metabolic pathways significantly correlated with age to develop personalized age-dependent PD blood biomarkers. RESULTS: We found 33 metabolites producing a receiver operating characteristic (ROC) area under the curve (AUC) value of 97%. PCA revealed that they belong to three pathways with distinct age-dependent behavior: glycine, threonine and serine metabolism correlates with age only in PD patients; unsaturated fatty acids biosynthesis correlates with age only in a healthy control group; and, finally, tryptophan metabolism characterizes PD but does not correlate with age. CONCLUSIONS: The targeted analysis of the blood metabolome proposed in this paper allowed to find specific age-related metabolites and metabolic pathways. The model offers a promising set of blood biomarkers for a personalized age-dependent approach to the early PD diagnosis.
RESUMO
Physical activity (PA) is a key element in the management of successful aging. The aim of this paper was to show the effects of PA on the quality of life perception, nutritional status, and daily life management of 178 older adults (aged 63.87 ± 8.17) randomly assigned to an Experimental Group (EG), which performed moderate-to-high intensity aerobic and strengthening training, and a Control Group (CG) which performed low-impact PA, assessed after 6, 12, and 24 months. The Short-Form Health Survey (SF-36), Mini Nutritional Assessment (MNA), and Physical Activity Scale for the Elderly (PASE) were used for the study. In the SF-36 assessment, EG showed a good quality of life perception maintained after 24 months, while CG showed a worsening in the same period (p = 0.018). The EG reported a significant better nutritional status as compared to pre-intervention assessment (p = 0.003) and to CG (p < 0.001). Regarding the PASE, the EG showed a higher level of weekly activities than the CG after 24 months (p = 0.011), while the CG showed a worsening after 12 months (p = 0.008). The prolonged engagement in moderate-to high-intensity PA allowed the maintenance of a good quality of life perception, a good level of nutritional status, and daily life activities.
Assuntos
Dieta Saudável , Qualidade de Vida , Idoso , Exercício Físico , Humanos , Avaliação Nutricional , PercepçãoRESUMO
Cystic fibrosis (CF) airways are affected by a deranged repair of the damaged epithelium resulting in altered regeneration and differentiation. Previously, we showed that human amniotic mesenchymal stem cells (hAMSCs) corrected base defects of CF airway epithelial cells via connexin (CX)43-intercellular gap junction formation. In this scenario, it is unknown whether hAMSCs, or fibroblasts sharing some common characteristics with MSCs, can operate a faster repair of a damaged airway epithelium. A tip-based scratch assay was employed to study wound repair in monolayers of CFBE14o- cells (CFBE, homozygous for the F508del mutation). hAMSCs were either co-cultured with CFBE cells before the wound or added to the wounded monolayers. NIH-3T3 fibroblasts (CX43+) were added to wounded cells. HeLa cells (CX43-) were used as controls. γ-irradiation was optimized to block CFBE cell proliferation. A specific siRNA was employed to downregulate CX43 expression in CFBE cells. CFBE cells showed a delayed repair as compared with wt-CFTR cells (16HBE41o-). hAMSCs enhanced the wound repair rate of wounded CFBE cell monolayers, especially when added post wounding. hAMSCs and NIH-3T3 fibroblasts, but not HeLa cells, increased wound closure of irradiated CFBE monolayers. CX43 downregulation accelerated CFBE wound repair rate without affecting cell proliferation. We conclude that hAMSCs and fibroblasts enhance the repair of a wounded CF airway epithelium, likely through a CX43-mediated mechanism mainly involving cell migration.
RESUMO
The CD33 gene encodes for a member of the sialic-acid-binding immunoglobulin-type lectin (Siglec) family, and is one of the top-ranked Alzheimer's disease (AD) risk genes identified by genome-wide association studies (GWAS). Many CD33 polymorphisms are associated with an increased risk of AD, but the function and potential mechanism of many CD33 single-nucleotide polymorphisms (SNPs) in promoting AD have yet to be elucidated. We recently identified the CD33 SNP rs2455069-A>G (R69G) in a familial form of dementia. Here, we demonstrate an association between the G allele of the rs2455069 gene variant and the presence of AD in a cohort of 195 patients from southern Italy. We carried out in silico analysis of the 3D structures of CD33 carrying the identified SNP to provide insights into its functional effect. Structural models of the CD33 variant carrying the R69G amino acid change were compared to the CD33 wild type, and used for the docking analysis using sialic acid as the ligand. Our analysis demonstrated that the CD33-R69G variant may bind sialic acid at additional binding sites compared to the wild type, thus potentially increasing its affinity/specificity for this molecule. Our results led to a new hypothesis of rs2455069-A>G SNP as a risk factor for AD, suggesting that a long-term cumulative effect of the CD33-R69G variant results from the binding of sialic acid, acting as an enhancer of the CD33 inhibitory effects on amyloid plaque degradation.
Assuntos
Doença de Alzheimer , Polimorfismo de Nucleotídeo Único , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Microglia/metabolismo , Ácido N-Acetilneuramínico/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genéticaRESUMO
Lipidomics is strategic in the discovery of biomarkers of neurodegenerative diseases (NDDs). The skin surface lipidome bears the potential to provide biomarker candidates in the detection of pathological processes occurring in distal organs. We investigated the sebum composition to search diagnostic and, possibly, prognostic, biomarkers of Alzheimer's disease (AD) and Parkinson's disease (PD). The observational study included 64 subjects: 20 characterized as "probable AD with documented decline", 20 as "clinically established PD", and 24 healthy subjects (HS) of comparable age. The analysis of sebum by GCMS and TLC retrieved the amounts (µg) of 41 free fatty acids (FFAs), 7 fatty alcohols (FOHs), vitamin E, cholesterol, squalene, and total triglycerides (TGs) and wax esters (WEs). Distributions of sebum lipids in NDDs and healthy conditions were investigated with multivariate ANOVA-simultaneous component analysis (ASCA). The deranged sebum composition associated with the PD group showed incretion of most composing lipids compared to HS, whereas only two lipid species (vitamin E and FOH14:0) were discriminant of AD samples and presented lower levels than HS sebum. Thus, sebum lipid biosynthetic pathways are differently affected in PD and AD. The characteristic sebum bio-signatures detected support the value of sebum lipidomics in the biomarkers search in NDDs.
RESUMO
Background: Alzheimer's disease (AD) is a devastating neurodegenerative disease without guidelines for early diagnosis or personalized treatment. Previous studies have highlighted a crucial role of increasing phosphorylation levels of the amyloid precursor protein (APP) Tyr682 residue in predicting neuronal deficits in AD patients. However, the lack of a method for the identification and quantification of Tyr682 phosphorylation levels prevents its potential clinical applications. Methods: Here we report a method to identify and quantify APP Tyr682 phosphorylation levels in blood mononuclear cells of AD patients by tandem mass spectrometry (tMS). Results: This method showed excellent sensitivity with detection and quantification limits set respectively at 0.035 and 0.082 ng injected for the phosphorylated peptide and at 0.02 and 0.215 ng injected for the non-phosphorylated peptide. The average levels of both peptides were quantified in transfected HELA cells (2.48 and 3.53 ng/µg of protein, respectively). Preliminary data on 3 AD patients showed quantifiable levels of phosphorylated peptide (0.10-0.15 ng/µg of protein) and below the LOQ level of non-phosphorylated peptide (0.13 ng/µg of protein). Conclusion: This method could allow the identification of patients with increased APP Tyr682 phosphorylation and allow early characterization of molecular changes prior to the appearance of clinical signs.
Assuntos
Precursor de Proteína beta-Amiloide/sangue , Leucócitos Mononucleares/metabolismo , Fosfoproteínas/metabolismo , Espectrometria de Massas em Tandem , Tirosina/metabolismo , Sequência de Aminoácidos , Precursor de Proteína beta-Amiloide/química , Calibragem , Linhagem Celular , Humanos , Fosforilação , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Alzheimer's disease (AD) is one of the most common causes of dementia in old people. Neuronal deficits such as loss of memory, language and problem-solving are severely compromised in affected patients. The molecular features of AD are Aß deposits in plaques or in oligomeric structures and neurofibrillary tau tangles in brain. However, the challenge is that Aß is only one piece of the puzzle, and recent findings continue to support the hypothesis that their presence is not sufficient to predict decline along the AD outcome. In this regard, metabolomic-based techniques are acquiring a growing interest for either the early diagnosis of diseases or the therapy monitoring. Mass spectrometry is one the most common analytical platforms used for detection, quantification, and characterization of metabolic biomarkers. In the past years, both targeted and untargeted strategies have been applied to identify possible interesting compounds. AIM OF REVIEW: The overall goal of this review is to guide the reader through the most recent studies in which LC-MS-based metabolomics has been proposed as a powerful tool for the identification of new diagnostic biomarkers in AD. To this aim, herein studies spanning the period 2009-2020 have been reported. Advantages and disadvantages of targeted vs untargeted metabolomic approaches have been outlined and critically discussed.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/diagnóstico , Biomarcadores , Cromatografia Líquida , Diagnóstico Precoce , Humanos , Metabolômica , Espectrometria de Massas em TandemRESUMO
Alzheimer's disease is a neurodegenerative disorder whose pathological mechanisms, despite recent advances, are not fully understood. However, the deposition of beta amyloid -peptide and neuroinflammation, which is probably aggravated by dysbiotic microbiota, seem to play a key role. Anti-Gal are the most abundant xenoreactive natural antibodies. They are supposed to stem from immunization against the gut microbiota and have been implicated in the pathogenesis of several diseases, including multiple sclerosis. These antibodies target the alpha-Gal epitope, expressed on the terminal sugar units of glycoprotein or glycolipid of all mammals except apes, Old World monkeys and humans. The alpha-Gal is constitutively expressed in several bacteria constituting the brain microbiota, and alpha-Gal-like epitopes have been detected in gray matter, amyloid plaque, neurofibrillary tangles and corpora amylacea of the human brain, suggesting a potential link between anti-Gal and Alzheimer's disease etiopathogenesis. For the first time, our study searched for possible alterations of anti-Gal immunoglobulin levels in Alzheimer's disease patients. IgG and IgM blood levels were significantly lower, and IgA significantly higher in patients than in healthy subjects. These results suggest that such immunoglobulins might be implicated in Alzheimer's disease pathogenesis and open new scenarios in the research for new biomarkers and therapeutic strategies.
RESUMO
Lippia citriodora is a plant traditionally used for its anti-inflammatory, antioxidant and antispasmodic effects, as well as for additional biological activities proven in cell culture, animal studies and a small number of human clinical trials. The plant has also shown a marked improvement in blood lipid profile in some animal species. In the present preliminary study, we investigated the effect of a leaf extract on lipid and oxidative blood profile of hypercholesterolemic volunteers. Twelve adults received Lippia citriodora extract caps, containing 23% phenylpropanoids, (100 mg, once a day) for 16 weeks. Selected blood lipids and plasma oxidative markers were measured at baseline and after 4, 8 and 16 weeks of treatment. Compared with baseline, total cholesterol levels significantly decreased and high-density lipoprotein cholesterol increased, while low-density lipoprotein cholesterol and triglycerides showed only a downward trend. Oxidative status was improved due to a decrease in the concentration of total oxidant status, reactive oxygen metabolites and malondialdehyde, and a significant increase in ferric reducing ability of plasma, vitamin A and vitamin E. These preliminary results suggest that dietary supplementation with Lippia citriodora extract can improve the lipid profile, enhance blood antioxidant power, and could be a valuable natural compound for the management of human hypercholesterolemia.
RESUMO
This work aims to assess the in vitro adhesion of two type strains of Lactobacillus plantarum (ATCC 14917 and ATCC BAA-793) (now Lactiplantibacillus plantarum). The experiments were conducted both in vitro on colon cells lines (Caco-2 and HT-29) and in vivo by adopting Galleria mellonella, a well-known alternative preclinical model. Data comparison obtained from in vitro and in vivo assays showed that adhesion performance is comparable in both models. Moreover, the type strain BAA-793, originally isolated from human saliva, showed enhanced adhesion performance, either in vitro to the low mucus-producing cell line (HT-29) or in vivo into the G mellonella gut. These results suggest a possible adaptation of this strain to its ecological niche compared to ATCC 14917. This preliminary pilot study, once again, showed the reliability of G. mellonella oral administration model as a first-line screening tool for in vitro to in vivo translation. Also, for the first time, the permanence of Lactobacillus strains into G. mellonella gut has been reported, reinforcing the claim that this preclinical model can be used, together with standardised in vitro and in vivo procedures already accepted across the scientific community, for the evaluation and investigation of new potential probiotic strains.
Assuntos
Lactobacillus plantarum , Lepidópteros , Probióticos , Administração Oral , Animais , Aderência Bacteriana , Células CACO-2 , Humanos , Projetos Piloto , Reprodutibilidade dos TestesRESUMO
In the context of biointeractive dressings used for enhancing wound healing, the use of stromal vascular fraction (SVF) or adipose-derived stem cells (ASCs) hereof derived has not been fully exploited yet. Noncultured SVF, a heterogeneous mesenchymal population of cells, is attractive in the field of dermal regeneration because it can be instantaneously obtained, avoids genomic alterations, and is comparatively safer than cultured ASCs. Integra® Dermal Regeneration Template (DRT) was sprinkled with ASCs in complete medium supplemented with 10% fetal bovine serum (FBS), or SVF, obtained from emulsified or nonemulsified fat, in medium supplemented with 2% platelet-rich plasma (PRP). The presence and differentiation of cells were evaluated by standard histochemistry and immunohistochemistry, whereas conditioned media were analyzed for vascular endothelial growth factors (VEGF) by ELISA. In vitro experiments were conducted to analyze ASC proliferation in the presence of either FBS or PRP. Deposition of ASCs in medium supplemented with FBS caused their integration into Integra DRT as early as 1 h. ASCs were found as aggregates until 6-10 days without forming organized structures. When seeded onto Integra DRT, SVF cells in medium supplemented with PRP formed aggregates at early times, which at 7 and 10 days organized into vascular-like structures, lined by CD31+ and smooth muscle actin-positive cells. With nonemulsified fat, the lacunar structures did not show an organized distribution of SVF cells. PRP induced ASC proliferation although at lower level than FBS. VEGF secretion was enhanced when fat emulsification was introduced into the protocol. In conclusion, the combination of SVF cells obtained from emulsified fat, PRP, and Integra DRT exhibit synergistic effect on the formation of vessel-like structures indicating a step forward aimed at regenerative surgery for chronic wound healing.
Assuntos
Tecido Adiposo , Plasma Rico em Plaquetas , Adipócitos , Células Cultivadas , Células-Tronco , CicatrizaçãoRESUMO
It is still debated whether non-specific preclinical symptoms of Alzheimer's disease (AD) can have diagnostic relevance. We followed the evolution from cognitively normal to AD by NMR-based metabolomics of blood sera. Multivariate statistical analysis of the NMR profiles yielded models that discriminated subjective memory decline (SMD), mild cognitive impairment (MCI) and AD. We validated a panel of six statistically significant metabolites that predicted SMD, MCI and AD in a blind cohort with sensitivity values ranging from 88 to 95% and receiver operating characteristic values from 0.88 to 0.99. However, lower values of specificity, accuracy and precision were observed for the models involving SMD and MCI, which is in line with the pathological heterogeneity indicated by clinical data. This excludes a "linear" molecular evolution of the pathology, pointing to the presence of overlapping "gray-zones" due to the reciprocal interference of the intermediate stages. Yet, the clear difference observed in the metabolic pathways of each model suggests that pathway dysregulations could be investigated for diagnostic purposes.
Assuntos
Doença de Alzheimer/classificação , Doença de Alzheimer/patologia , Biomarcadores/sangue , Disfunção Cognitiva/patologia , Idoso , Doença de Alzheimer/sangue , Disfunção Cognitiva/sangue , Progressão da Doença , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Curva ROCRESUMO
Sialic acid-binding immunoglobulin-type lectins, which are predominantly expressed in immune cells, represent a family of immunomodulatory receptors with inhibitory and activating signals, in both healthy and disease states. Genetic factors are important in all forms of dementia, especially in early onset dementia. CD33 was recently recognized as a genetic risk factor for Alzheimer disease (AD). Here, we present a 2-generation family with 4 members, the father and the 3 siblings, characterized by an early form of unusual dementia exhibiting a behavioral variant close to behavioral variant frontotemporal dementia phenotype and severe forms of memory loss suggestive of AD. We analyzed the CD33 gene in this family and identified 10 single nucleotide polymorphisms (SNPs) in a linkage disequilibrium block associated with the disease. We also identified a tag SNP, rs2455069-A>G, in CD33 exon 2 that could be involved with dementia risk. Additionally, we excluded the presence of C9orf72 expansion mutations and other mutations previously associated with sporadic FTD and AD. The tag SNP association was also analyzed in selected sporadic AD patients from the same Southern Italy region. We demonstrate that CD33 and SIGLECL1 have a significantly increased level of expression in these patients.
Assuntos
Demência/genética , Predisposição Genética para Doença/genética , Lectinas/genética , Proteínas de Membrana/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The continuous improvements in the field of both regenerative medicine and tissue engineering have allowed the design of new and more efficacious strategies for the treatment of chronic or hard-to-heal skin wounds, which represent heavy burden, from a medical and economic point of view. These novel approaches are based on the usage of three key methodologies: stem cells, growth factors, and biomimetic scaffolds. These days, the adipose tissue can be considered the main source of multipotent mesenchymal stem cells, especially adipose-derived stem cells (ASCs). ASCs are easily accessible from various fat depots and show an intrinsic plasticity in giving rise to cell types involved in wound healing and angiogenesis. ASCs can be found in fat grafts, historically used in the treatment of chronic wounds, and have been evaluated as such in both animal models and human trials, to exploit their capability of accelerating wound closure and inducing a correct remodeling of the newly formed fibrovascular tissue. Since survival and fitness of ASCs need to be improved, they are now employed in conjunction with advanced wound dressings, together with dermal regenerative templates and platelet-rich plasma (as a source of growth and healing factors). In this work, we provide an overview of the current knowledge on the topic, based on existing studies and on our own experience.
RESUMO
BACKGROUND: Several observational studies have shown that exercise reduces the risk of cognitive decline; however, evidences from long-term, well-conducted, randomized controlled trials are scanty. The principal aim of this study is to verify whether a long-term program of multimodal supervised exercise improves the cognitive function and/or reduces the rate of cognitive decline in older adults at different degrees of risk for dementia. METHODS/DESIGN: EPD is a parallel group, double-blind, randomized controlled trial. Community-dwelling volunteers aged 50 years or more are being recruited from different community centers and screened for eligibility. Enrolled subjects are being divided in 3 groups: a) without subjective or objective cognitive impairment, b) with subjective memory complaints, and c) with mild cognitive impairments. Participants in each group (at least 180) are being randomly assigned (1:1) to an experimental group, performing a supervised training including aerobic and resistance exercises of moderate/high intensity, or to a control group. Primary outcome will be 48-months changes in Mini Mental State Examinations. Secondary outcomes will be changes in several cognitive tests including a composite cognitive score. Time points will be at baseline, and at 6, 12, 24, 36 and 48 months. Statistical analysis will be done as intention to treat, complete case and mixed model analysis. DISCUSSION: EPD is the first trial to examine the effects of a long exercise program (48 months) on cognitive performances. If successful, this trial may provide evidence for using long-term and multimodal exercise interventions for dementia prevention programs in the aging population. TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov with the code NCT02236416 .