Metabolic syndrome and the risk of late onset Alzheimer's disease: An updated review and meta-analysis.

AIMS: This study aims to provide an updated systematic review and meta-analysis on the risk of Alzheimer's disease (AD) in patients with metabolic syndrome (MetS) and to analyze the contribution of each MetS component on AD onset. DATA SYNTHESIS: The study was performed according to the PRISMA guideline. Data were obtained searching MEDLINE, Scopus, Web of Science, and EMBASE for studies published between January 1, 2010 and July 30, 2020, evaluating the association between MetS and AD risk. A total of 255 articles were retrieved and 6 investigations (4 prospective and 2 retrospective) met the inclusion criteria. Overall, 9.788.021 patients with a mean follow-up of 4.5 years were analyzed. The pooled analysis revealed a slight increased risk of AD in MetS (hazard ratio, HR: 1.10, 95% and confidence interval, CI: 1.05-1.15). Egger's test indicated the absence of publication bias (t = 2.095 and p = 0.104). However, while analysis based on prospective studies failed to show a significant association between MetS and AD (HR: 0.80 and 95% CI: 0.61-1.05), analysis based on retrospective studies demonstrated a significant, slight increased risk (HR:1.11 and 95% CI: 1.08-1.66). With regard to MetS components, the risk was: arterial hypertension, HR: 1.05 (95% CI: 1.04-10.6); hyperglycemia/diabetes, HR: 1.19 (95% CI: 1.18-1.99); low high-density lipoprotein cholesterol (HDL-C), HR: 1.07 (95% CI: 1.06-1.07); hypertriglyceridemia, HR: 1.06 (95% CI: 1.05-1.06); and abdominal obesity, HR: 0.84 (95% CI: 0.74-0.95). CONCLUSIONS: We found a significant association between MetS and AD, mainly driven by large retrospective studies. Our data also support the association of single MetS components with AD incidence, while increased waist circumference seems to have a "protective role" probably due to reverse causality.

PPARγ Pro12Ala and ACE ID polymorphisms are associated with BMI and fat distribution, but not metabolic syndrome.

BACKGROUND: Metabolic Syndrome (MetS) results from the combined effect of environmental and genetic factors. We investigated the possible association of peroxisome proliferator-activated receptor-γ2 (PPARγ2) Pro12Ala and Angiotensin Converting Enzyme (ACE) I/D polymorphisms with MetS and interaction between these genetic variants. METHODS: Three hundred sixty four unrelated Caucasian subjects were enrolled. Waist circumference, blood pressure, and body mass index (BMI) were recorded. Body composition was estimated by impedance analysis; MetS was diagnosed by the NCEP-ATPIII criteria. A fasting blood sample was obtained for glucose, insulin, lipid profile determination, and DNA isolation for genotyping. RESULTS: The prevalence of MetS did not differ across PPARγ2 or ACE polymorphisms. Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but lower systolic blood pressure compared with Pro/Pro homozygotes. A significant PPARγ2 gene-gender interaction was observed in the modulation of BMI, fat mass, and blood pressure, with significant associations found in women only. A PPARγ2-ACE risk genotype combination for BMI and fat mass was found, with ACE DD/PPARγ2 Ala subjects having a higher BMI (p = 0.002) and Fat Mass (p = 0.002). Pro12Ala was independently associated with waist circumference independent of BMI and gender. CONCLUSIONS: Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but not a worse metabolic profile, possibly because of a more favorable adipose tissue distribution. A gene interaction exists between Pro12Ala and ACE I/D on BMI and fat mass. Further studies are needed to assess the contribution of Pro12Ala polymorphism in adiposity distribution.

Oral Microbiome Dysbiosis Is Associated With Symptoms Severity and Local Immune/Inflammatory Response in COVID-19 Patients: A Cross-Sectional Study.

The human oral microbiome (HOM) is the second largest microbial community after the gut and can impact the onset and progression of several localized and systemic diseases, including those of viral origin, especially for viruses entering the body via the oropharynx. However, this important aspect has not been clarified for the new pandemic human coronavirus SARS-CoV-2, causing COVID-19 disease, despite it being one of the many respiratory viruses having the oropharynx as the primary site of replication. In particular, no data are available about the non-bacterial components of the HOM (fungi, viruses), which instead has been shown to be crucial for other diseases. Consistent with this, this study aimed to define the HOM in COVID-19 patients, to evidence any association between its profile and the clinical disease. Seventy-five oral rinse samples were analyzed by Whole Genome Sequencing (WGS) to simultaneously identify oral bacteria, fungi, and viruses. To correlate the HOM profile with local virus replication, the SARS-CoV-2 amount in the oral cavity was quantified by digital droplet PCR. Moreover, local inflammation and secretory immune response were also assessed, respectively by measuring the local release of pro-inflammatory cytokines (L-6, IL-17, TNFα, and GM-CSF) and the production of secretory immunoglobulins A (sIgA). The results showed the presence of oral dysbiosis in COVID-19 patients compared to matched controls, with significantly decreased alpha-diversity value and lower species richness in COVID-19 subjects. Notably, oral dysbiosis correlated with symptom severity (p = 0.006), and increased local inflammation (p < 0.01). In parallel, a decreased mucosal sIgA response was observed in more severely symptomatic patients (p = 0.02), suggesting that local immune response is important in the early control of virus infection and that its correct development is influenced by the HOM profile. In conclusion, the data presented here suggest that the HOM profile may be important in defining the individual susceptibility to SARS-CoV-2 infection, facilitating inflammation and virus replication, or rather, inducing a protective IgA response. Although it is not possible to determine whether the alteration in the microbial community is the cause or effect of the SARS-CoV-2 replication, these parameters may be considered as markers for personalized therapy and vaccine development.

Anti-SARS-Cov-2 IgA Response in Tears of COVID-19 Patients.

The pandemic virus SARS-CoV-2 has been reported to be able to enter the body via the eye conjunctiva, but the presence of antiviral response in the eye remains poorly known. Our study was thus aimed to analyze the presence of secretory mucosal anti-SARS-CoV-2 type A immunoglobulins (IgA) in the conjunctival fluid of COVID-19 patients. The tears of 28 COVID-19 patients and 20 uninfected controls were collected by the Schirmer test and analyzed by a specific ELISA assay detecting anti-spike (S1) virus protein IgA. The results showed that 35.7% of COVID-19 subjects have specific antiviral IgA at the ocular level, persisting till 48 days post disease onset. Most of the IgA positive subjects presented mild symptoms. The collected data indicate a prolonged persistence of anti-SARS-CoV-2 IgA at the eye level and suggest that IgA detection may be extremely helpful in clarifying virus pathology and epidemiology.

Brain-derived neurotrophic factor plasma levels: relationship with dementia and diabetes in the elderly population.

The mechanisms linking diabetes and cognitive impairment/dementia, two common conditions of elderly people, are not completely known. Brain-derived neurotrophic factor (BDNF) has antidiabetic properties, and reduced circulating BDNF was associated with dementia. We investigated the relationship between plasma BDNF levels, dementia, and diabetes in a sample of 164 community-dwelling elderly individuals, including 50 participants with vascular dementia, 44 with late onset Alzheimer's disease, 23 with cerebrovascular disease not dementia, and 47 controls (C). Presence/absence of diabetes was registered; new diagnoses of diabetes were made by the American Diabetes Association criteria. BDNF plasma levels were measured by ELISA. Both diagnosis of dementia and diabetes were associated with lower BDNF plasma values compared with the respective controls; moreover, dementia and diabetes correlated with BDNF plasma levels, independent of possible confounders. A progressive reductions of BDNF plasma levels from C (383.9 ± 204.6 pg/mL), to cerebrovascular disease not dementia (377.1 ± 130.2), to vascular dementia (313.3 ± 114.8), to late onset Alzheimer's disease (264.7 ± 147.7) was observed, (late onset Alzheimer's disease vs C, p: .03; late onset Alzheimer's disease vs cerebrovascular disease not dementia, p: .002). Demented patients affected by diabetes had the lowest BDNF mean levels (264.9 pg/mL) among individuals enrolled in this sample, suggesting the existence of a "synergistic" effect of dementia and diabetes on BDNF levels.

Diagnostic and prognostic microRNAs in the serum of breast cancer patients measured by droplet digital PCR.

BACKGROUND: Breast cancer circulating biomarkers include carcinoembryonic antigen and carbohydrate antigen 15-3, which are used for patient follow-up. Since sensitivity and specificity are low, novel and more useful biomarkers are needed. The presence of stable circulating microRNAs (miRNAs) in serum or plasma suggested a promising role for these tiny RNAs as cancer biomarkers. To acquire an absolute concentration of circulating miRNAs and reduce the impact of preanalytical and analytical variables, we used the droplet digital PCR (ddPCR) technique. RESULTS: We investigated a panel of five miRNAs in the sera of two independent cohorts of breast cancer patients and disease-free controls. The study showed that miR-148b-3p and miR-652-3p levels were significantly lower in the serum of breast cancer patients than that in controls in both cohorts. For these two miRNAs, the stratification of breast cancer patients versus controls was confirmed by receiver operating characteristic curve analyses. In addition, we showed that higher levels of serum miR-10b-5p were associated with clinicobiological markers of poor prognosis. CONCLUSIONS: The study revealed the usefulness of the ddPCR approach for the quantification of circulating miRNAs. The use of the ddPCR quantitative approach revealed very good agreement between two independent cohorts in terms of comparable absolute miRNA concentrations and consistent trends of dysregulation in breast cancer patients versus controls. Overall, this study supports the use of the quantitative ddPCR approach for monitoring the absolute levels of diagnostic and prognostic tumor-specific circulating miRNAs.

Defective P2Y purinergic receptor function: A possible novel mechanism for impaired glucose transport.

Extracellular ATP is an ubiquitous mediator that regulates several cellular functions via specific P2 plasma membrane receptors (P2Rs), for which a role in modulating intracellular glucose metabolism has been recently suggested. We have investigated glucose uptake in response to P2Rs stimulation in fibroblasts from type 2 diabetic (T2D) patients and control subjects. P2Rs expression was evaluated by RT-PCR; intracellular calcium release by fluorometry; glucose transporter (GLUT1) translocation by immunoblotting and chemiluminescence; glucose uptake was measured with 2-deoxy-D-[1-(3)H]glucose (2-DOG) and ATP by luminometry. Cells from T2D patients, in contrast to those from healthy controls, showed no increase in glucose uptake after ATP stimulation; extracellular ATP caused, however, a similar GLUT1 recruitment to the plasma membrane in both groups. P2Rs expression did not differ between fibroblasts from diabetic and healthy subjects, but while plasma membrane depolarization, a P2X-mediated response was similar in both groups, no evident intracellular calcium increase was detectable in the cells from the former group. The calcium response in fibroblasts from diabetics was restored by co-incubation with apyrase or hexokinase, suggesting that P2YRs in those cells were normally expressed but chronically desensitised. In support to this finding, fibroblasts from T2D subjects secreted a two-fold larger amount of ATP compared to controls. Pre-treatment with apyrase or hexokinase also restored ATP stimulated glucose uptake in fibroblasts from diabetic subjects. These results suggest that extracellular ATP plays a role in the modulation of glucose transport via GLUT1, and that the P2Y-dependent GLUT1 activation is deficient in fibroblasts from T2D individuals. Our observations may point to additional therapeutic targets for improving glucose utilization in diabetes.