Schizophrenia and Glutathione: A Challenging Story.

Schizophrenia (SZ) is a devastating mental illness with a complex and heterogeneous clinical state. Several conditions like symptoms, stage and severity of the disease are only some of the variables that have to be considered to define the disorder and its phenotypes. SZ pathophysiology is still unclear, and the diagnosis is currently relegated to the analysis of clinical symptoms; therefore, the search for biomarkers with diagnostic relevance is a major challenge in the field, especially in the era of personalized medicine. Though the mechanisms implicated in SZ are not fully understood, some processes are beginning to be elucidated. Oxidative stress, and in particular glutathione (GSH) dysregulation, has been demonstrated to play a crucial role in SZ pathophysiology. In fact, glutathione is a leading actor of oxidative-stress-mediated damage in SZ and appears to reflect the heterogeneity of the disease. The literature reports differing results regarding the levels of glutathione in SZ patients. However, each GSH state may be a sign of specific symptoms or groups of symptoms, candidating glutathione as a biomarker useful for discriminating SZ phenotypes. Here, we summarize the literature about the levels of glutathione in SZ and analyze the role of this molecule and its potential use as a biomarker.

Cause or consequence? The role of IL-1 family cytokines and receptors in neuroinflammatory and neurodegenerative diseases.

Cytokines and receptors of the IL-1 family are key mediators in innate immune and inflammatory reactions in physiological defensive conditions, but are also significantly involved in immune-mediated inflammatory diseases. Here, we will address the role of cytokines of the IL-1 superfamily and their receptors in neuroinflammatory and neurodegenerative diseases, in particular Multiple Sclerosis and Alzheimer's disease. Notably, several members of the IL-1 family are present in the brain as tissue-specific splice variants. Attention will be devoted to understanding whether these molecules are involved in the disease onset or are effectors of the downstream degenerative events. We will focus on the balance between the inflammatory cytokines IL-1ß and IL-18 and inhibitory cytokines and receptors, in view of future therapeutic approaches.

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease.

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-ß precursor protein processing, amyloid-ß aggregation, lipid metabolism and microglial function in AD.

Targeting NAAA counters dopamine neuron loss and symptom progression in mouse models of parkinsonism.

The lysosomal cysteine hydrolase N-acylethanolamine acid amidase (NAAA) deactivates palmitoylethanolamide (PEA), a lipid-derived PPAR-α agonist that is critically involved in the control of pain and inflammation. In this study, we asked whether NAAA-regulated PEA signaling might contribute to dopamine neuron degeneration and parkinsonism induced by the mitochondrial neurotoxins, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In vitro experiments showed that 6-OHDA and MPTP enhanced NAAA expression and lowered PEA content in human SH-SY5Y cells. A similar effect was observed in mouse midbrain dopamine neurons following intra-striatal 6-OHDA injection. Importantly, deletion of the Naaa gene or pharmacological inhibition of NAAA activity substantially attenuated both dopamine neuron death and parkinsonian symptoms in mice treated with 6-OHDA or MPTP. Moreover, NAAA expression was elevated in postmortem brain cortex and premortem blood-derived exosomes from persons with Parkinson's disease compared to age-matched controls. The results identify NAAA-regulated PEA signaling as a molecular control point for dopaminergic neuron survival and a potential target for neuroprotective intervention.

IL-33 and IL-10 Serum Levels Increase in MCI Patients Following Homotaurine Treatment.

Homotaurine is a potential therapeutic compound for treatment of Alzheimer's disease (AD), but its efficacy is still under investigation. Emerging data have shown that other than neuroprotective, homotaurine is endowed with anti-inflammatory activities, though with still unclear underlying mechanisms. Inflammation plays a critical role in the pathogenesis of AD and we previously suggested that homotaurine supplementation in patients with amnestic mild cognitive impairment (MCI) plays beneficial effects associated to a decrease in the circulating levels of the pro-inflammatory cytokine IL-18. Here we report that MCI patients supplemented with homotaurine for 12 months show elevated serum levels of IL-10 and IL-33, as compared to baseline, in addition to the described IL-18 decrease. Furthermore, we observed a significant positive correlation between IL-10 and IL-33 levels after treatment but not at the baseline, underlining the effectiveness of the compound in modulating both cytokines in an inter-related fashion and in regulating the pro/anti-inflammation balance. Furthermore, the elevation of both IL-10 and IL-33 is significantly associated with an improvement of episodic memory of treated patients, as measured by the Delayed Verbal Ray Test. In conclusion, our results confirm that homotaurine treatment exerts an overall anti-inflammatory action in MCI patients, based not only on the down-regulation of pro-inflammatory IL-18, but also on up-regulation of the anti-inflammatory IL-33 and IL-10 cytokines, which in turn are associated with an amelioration of patient's cognitive functions. Future studies should be addressed to investigate the molecular mechanisms of homotaurine anti-inflammatory activity and its therapeutic exploitation in early AD.

Identification of Genetic Networks Reveals Complex Associations and Risk Trajectory Linking Mild Cognitive Impairment to Alzheimer's Disease.

Amnestic mild cognitive impairment (aMCI) and sporadic Alzheimer's disease (AD) are multifactorial conditions resulting from a complex crosstalk among multiple molecular and biological processes. The present study investigates the association of variants localized in genes and miRNAs with aMCI and AD, which may represent susceptibility, prognostic biomarkers or multi-target treatment options for such conditions. We included 371 patients (217 aMCI and 154 AD) and 503 healthy controls, which were genotyped for a panel of 120 single nucleotide polymorphisms (SNPs) and, subsequently, analyzed by statistical, bioinformatics and machine-learning approaches. As a result, 21 SNPs were associated with aMCI and 13 SNPs with sporadic AD. Interestingly, a set of variants shared between aMCI and AD displayed slightly higher Odd Ratios in AD with respect to aMCI, highlighting a specific risk trajectory linking aMCI to AD. Some of the associated genes and miRNAs were shown to interact within the signaling pathways of APP (Amyloid Precursor Protein), ACE2 (Angiotensin Converting Enzyme 2), miR-155 and PPARG (Peroxisome Proliferator Activated Receptor Gamma), which are known to contribute to neuroinflammation and neurodegeneration. Overall, results of this study increase insights concerning the genetic factors contributing to the neuroinflammatory and neurodegenerative mechanisms underlying aMCI and sporadic AD. They have to be exploited to develop personalized approaches based on the individual genetic make-up and multi-target treatments.

A metabolic biomarker predicts Parkinson's disease at the early stages in patients and animal models.

BackgroundCare management of Parkinson's disease (PD) patients currently remains symptomatic, mainly because diagnosis relying on the expression of the cardinal motor symptoms is made too late. Earlier detection of PD therefore represents a key step for developing therapies able to delay or slow down its progression.MethodsWe investigated metabolic markers in 3 different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 3 cohorts of de novo PD patients and matched controls (n = 129). Serum and brain tissue samples were analyzed by nuclear magnetic resonance spectroscopy and data submitted to advanced multivariate statistics.ResultsOur translational strategy reveals common metabolic dysregulations in serum of the different animal models and PD patients. Some of them were mirrored in the tissue samples, possibly reflecting pathophysiological mechanisms associated with PD development. Interestingly, some metabolic dysregulations appeared before motor symptom emergence and could represent early biomarkers of PD. Finally, we built a composite biomarker with a combination of 6 metabolites. This biomarker discriminated animals mimicking PD from controls, even from the first, nonmotor signs and, very interestingly, also discriminated PD patients from healthy subjects.ConclusionFrom our translational study, which included 3 animal models and 3 de novo PD patient cohorts, we propose a promising biomarker exhibiting a high accuracy for de novo PD diagnosis that may possibly predict early PD development, before motor symptoms appear.FundingFrench National Research Agency (ANR), DOPALCOMP, Institut National de la Santé et de la Recherche Médicale, Université Grenoble Alpes, Association France Parkinson.

The Anti-SARS-CoV-2 Antibody Response in a Centenarian Woman: A Case of Long-Term Memory?

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic, causing respiratory syndrome and other manifestations. The clinical consequences of the SARS-CoV-2 infection are highly heterogeneous, ranging from asymptomatic and mild to severe and fatal conditions, with the highest mortality rate reached among elderly people. Such heterogeneity appears strongly influenced by the host immune response, which in turn is profoundly affected by aging. In fact, the occurrence of a low-grade inflammation and a decline in specific immune defense is generally reported in older people. Although the low ability of B cells to provide primary and secondary specific responses with a consequent increase in susceptibility to and severity of virus infections is generally described in elderly people, we would like to present here the particular case of a 100-year-old woman, who recovered well from COVID-19 and developed a long-term memory against SARS-CoV-2. Following the infection, the patient's blood was tested with both a classical ELISA and a specific Cell-ELISA addressed to measure the anti-spike S1 specific IgG released in plasma or produced in vitro by memory B cells, respectively. While showing negative on classical serological testing, the patient's blood was positive in Cell-ELISA up to 1 year after the infection. Our observation highlights a potential mechanism of B cell-dependent, long-term protection in response to SARS-CoV-2 infection, suggesting that in a case of successful aging, the absence of specific antibodies in serum does not necessarily mean the absence of immune memory.

Immune System and Neuroinflammation in Idiopathic Parkinson's Disease: Association Analysis of Genetic Variants and miRNAs Interactions.

The present study investigated the association of SNPs involved in the regulation of immune response, cellular degenerative and neuroinflammatory pathways with the susceptibility and progression of idiopathic Parkinson's Disease (PD). In particular, 342 PD patients were subjected to a genotyping analysis of a panel of 120 SNPs by Open Array Technology. As control group, 503 samples representative of the European general population were utilized. The genetic analysis identified 26 SNPs associated with PD susceptibility. Of them, 12 SNPs were described as significant expression Quantitative Loci (eQTL) variants in different brain regions associated with motor and non-motor PD phenomenology. Moreover, the study highlighted 11 novel susceptibility genes for PD, which may alter multiple signaling pathways critically involved in peripheral immune response, neuroinflammation, neurodegeneration and dopaminergic neurons wiring. The study of miRNA-target genes highlighted a possible role of miR-499a, miR-196a2, and miR-29a in the modulation of multiple neuroinflammatory and neurodegenerative mechanisms underlying PD physiopathology. The study described a network of interconnected genes (APOE, CLU, IL6, IL7R, IL12B, INPP5D, MAPK1, MEF2C, MIF, and TNFSF14), which may act as upstream regulators in the modulation of biological pathways relevant to PD. Intriguingly, IL6 stands out as a master gene regulator since it may indirectly regulate the network of interconnected genes. The study highlighted different genes and miRNAs interactions potentially involved in PD physiopathology, which are worth to be further explored to improve the knowledge of disease and the research of novel treatments strategies.

A Cell-Based ELISA to Improve the Serological Analysis of Anti-SARS-CoV-2 IgG.

Knowledge of the antibody-mediated immune response to SARS-CoV-2 is crucial to understand virus immunogenicity, establish seroprevalence, and determine whether subjects or recovered patients are at risk for infection/reinfection and would therefore benefit from vaccination. Here, we describe a novel and simple cell-ELISA specifically designed to measure viral spike S1-specific IgG produced in vitro by B cells in peripheral blood mononuclear cell (PBMC) cultures from a cohort of 45 asymptomatic (n = 24) and symptomatic (n = 21) individuals, with age ranging from 8 to 99 years. All subjects underwent ELISA serological screening twice, at the same time as the cell-ELISA (T2) as well as 35-60 days earlier (T1). Cryopreserved PBMCs of healthy donors obtained years before the COVID-19 pandemic were also included in the analysis. The preliminary results presented here show that out of 45 tested subjects, 16 individuals (35.5%) were positive to the cell-ELISA, 11 (24.5%) were concomitantly positive in the serological screening (T1 and/or T2), and only one person was exclusively positive in ELISA (T1) and negative in cell-ELISA, though values were close to the cutoff. Of note, five individuals (11.2%) tested negative in ELISA but positive in cell-ELISA and thus, they appear to have circulating B cells that produce antibodies against SARS-CoV-2, likely at levels that are undetectable in the serum, which challenges the negative results of the serological screening. The relative level of in vitro secreted IgG was measurable in positive subjects, ranging from 7 to 50 ng/well. Accordingly, all anti-SARS-CoV-2 antibody-positive subjects previously reported moderate to severe symptoms attributable to COVID-19, even though the RT-PCR data were rarely available to confirm viral infection. Overall, the described cell-ELISA might be an effective method for detecting subjects who encountered the virus in the past, and thus helpful to improve serological ELISA tests in the case of undetectable/equivocal circulating IgG levels, and a suitable and improved tool to better evaluate SARS-CoV-2-specific humoral immunity in the COVID-19 pandemic.

Implication of Aging Related Chronic Neuroinflammation on COVID-19 Pandemic.

SARS-CoV-2, the virus responsible for the COVID-19 pandemic, leads to a respiratory syndrome and other manifestations. Most affected people show no or mild symptoms, but the risk of severe disease and death increases in older people. Here, we report a narrative review on selected studies targeting aging-related chronic neuroinflammation in the COVID-19 pandemic. A hyperactivation of the innate immune system with elevated levels of pro-inflammatory cytokines occurs during severe COVID-19, pointing to an important role of the innate immune dysregulation in the disease outcome. Aging is characterized by a general condition of low-grade inflammation, also connected to chronic inflammation of the brain (neuroinflammation), which is involved in frailty syndrome and contributes to several age-associated diseases, including neurodegenerative and neuropsychiatric disorders. Since neuroinflammation can be induced or worsened by the virus infection itself, as well as by stressful conditions like those linked to the recent pandemic, the role of neuroinflammatory mechanisms could be central in a vicious circle leading to an increase in the mortality risk in aged COVID-19 patients. Furthermore, triggered neuroinflammatory pathways and consequent neurodegenerative and neuropsychiatric conditions might be potential long-term complications of COVID-19. In order to provide insights to help clinicians in identifying patients who progress to a more severe case of the disease, this review underlines the potential implications of aging-related neuroinflammation in COVID-19 pandemic.

CD33 and SIGLECL1 Immunoglobulin Superfamily Involved in Dementia.

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.

Is Innate Memory a Double-Edge Sword in Alzheimer's Disease? A Reappraisal of New Concepts and Old Data.

An emergent concept in immunology suggests that innate immune system is capable to undergo non-specific long-term responses and to provide resistance by modifying the reactivity to sequential pathogen challenge. This phenomenon, named innate memory, involves epigenetic, and metabolic reprogramming of innate immune cells. Current literature shows that the innate memory process has a mainly beneficial role in host defense, but sometimes can exert detrimental effects, as common in many diseases. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and dementia. Accumulating findings demonstrate that inflammation is involved in AD pathogenesis and progression and recent genetic and functional data confirm the driving role of the innate immune component in the disease. Furthermore, AD patients show high burden of the most relevant infectious agents and up-regulation of inflammatory features in their innate immune cells, including an activated, or "primed" status of myeloid phagocytic cells in both brain and periphery, resembling trained immunity conditions. Thus, it is conceivable that AD innate cells may be firstly involved in the attempt to resolve recurrent/persistent inflammation but then acquire a trained phenotype mostly unable to maintain the immune regulation, leaving uncontrolled or sometimes supporting the progression of neurodegeneration. The present review aims to summarize evidence evoking innate immune memory mechanisms in AD, and to interpret their potential role, either protective or harmful, in disease progression. A better understanding of such mechanisms will provide a fertile ground for development of novel diagnostic, and therapeutic pathways in AD cure.

Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease.

Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.

Neurovascular Dysfunction in Alzheimer Disease: Assessment of Cerebral Vasoreactivity by Ultrasound Techniques and Evaluation of Circulating Progenitor Cells and Inflammatory Markers.

AIMS: The aims of this study were to assess vascular dysfunction in patients with Alzheimer disease (AD) by investigating cerebral vasomotor reactivity using transcranial Doppler ultrasound (TCD) and to evaluate any correlations between cerebral vasoreactivity and endothelium dysfunction. Moreover, the frequency of circulating progenitor cells (CPCs) and the blood concentration of vascular/inflammatory markers were evaluated. MATERIALS AND METHODS: We recruited 35 AD subjects and 17 age-matched, sex-matched, and education-matched healthy control subjects. Cerebral vasomotor reactivity was assessed by means of the TCD-based breath-holding index test (BHI). The level of CPCs was evaluated by means of flow cytometry from venous blood samples, while blood vascular/inflammatory markers were measured by means of enzyme-linked immunosorbent assay. RESULTS: Both cerebral assay blood flow velocity in the middle cerebral artery (MCAFV) and BHI values were significantly lower in AD subjects than in healthy controls (P<0.05). A positive trend was found between MCAFV and BHI values and Mini-Mental State Evaluation (MMSE) scores. Moreover, the hematopoietic progenitor cells' count was found to be lower in patients with AD than in controls (P<0.05). Finally, a significantly higher expression of the plasma chemokine CCL-2 was observed in AD patients than in healthy controls. CONCLUSIONS: Our results confirm that cerebral hemodynamic deterioration may be a critical marker of cognitive decline. Further studies are needed to investigate the role of circulating CPCs and chemokines as potential contributors to neurovascular dysfunction.

Gender specific decrease of a set of circulating N-acylphosphatidyl ethanolamines (NAPEs) in the plasma of Parkinson's disease patients.

INTRODUCTION: Current markers of Parkinson's disease (PD) fail to detect the early progression of disease state. Conversely, current omics techniques allow the investigation of hundreds of molecules potentially altered by disease conditions. Based on evidence previously collected by our group in a mouse model of PD, we speculated that a particular set of circulating lipids might be significantly altered by the pathology. OBJECTIVES: The aim of current study was to evaluate the potential of a particular set of N-acyl-phosphatidylethanolamines (NAPEs) as potential non-invasive plasma markers of ongoing neurodegeneration from Parkinson's disease in human subjects. METHODS: A panel of seven NAPEs were quantified by LC-MS/MS in the plasma of 587 individuals (healthy controls, n = 319; Parkinson's disease, n = 268); Random Forest classification and statistical modeling was applied to compare Parkinson's disease versus controls. All p-values obtained in different tests were corrected for multiplicity by controlling the false discovery rate (FDR). RESULTS: The results indicate that this panel of NAPEs is able to distinguish female PD patients from the corresponding healthy controls. Further to this, the observed downregulation of these NAPEs is in line with the results in plasma of a mouse model of Parkinson's (6-OHDA). CONCLUSIONS: In the current study we have shown the downregulation of NAPEs in plasma of PD patients and we thus speculate that these lipids might serve as candidate biomarkers for PD. We also suggest a molecular mechanism, explaining our findings, which involves gut microbiota.

Polygenic risk and hazard scores for Alzheimer's disease prediction.

Objective: Genome-wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age-specific genetic risk for AD. The aim of this study was to quantify the age-specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS. Methods: Quantification of individual differences in age-specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age-specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs P-value thresholds for disease association. Results: Polygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at P ≤ 0.001. The strongest effect (B = 0.28, SE = 0.04, P = 2.5 × 10-12) was observed for PRS based upon genome-wide significant SNPs (P ≤ 5 × 10-8). The strength of association was weaker with less stringent SNP selection thresholds. Interpretation: Both PRS and PHS can be used to predict an age-specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control P ≤ 10-3, we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at P > 10-3, the age-specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study).

Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease.

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer's disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.

Elevated plasma ceramide levels in post-menopausal women: a cross-sectional study.

Circulating ceramide levels are abnormally elevated in age-dependent pathologies such as cardiovascular diseases, obesity and Alzheimer's disease. Nevertheless, the potential impact of age on plasma ceramide levels has not yet been systematically examined. In the present study, we quantified a focused panel of plasma ceramides and dihydroceramides in a cohort of 164 subjects (84 women) 19 to 80 years of age. After adjusting for potential confounders, multivariable linear regression analysis revealed a positive association between age and ceramide (d18:1/24:0) (ß (SE) = 5.67 (2.38); p = .0198) and ceramide (d18:1/24:1) (ß (SE) = 2.88 (.61); p < .0001) in women, and between age and ceramide (d18:1/24:1) in men (ß (SE) = 1.86 (.77); p = .0179). In women of all ages, but not men, plasma ceramide (d18:1/24:1) was negatively correlated with plasma estradiol (r = -0.294; p = .007). Finally, in vitro experiments in human cancer cells expressing estrogen receptors showed that incubation with estradiol (10 nM, 24 h) significantly decreased ceramide accumulation. Together, the results suggest that aging is associated with an increase in circulating ceramide levels, which in post-menopausal women is at least partially associated with lower estradiol levels.

Anti-inflammatory Effects of Homotaurine in Patients With Amnestic Mild Cognitive Impairment.

Alzheimer's disease (AD) is a fatal dementing neurodegenerative disease, currently lacking an efficacious disease-modifying therapy. In the last years, there has been some interest in the use of homotaurine as a potential therapeutic compound for AD, but more work is still needed to prove its efficacy as disease modifier in dementia. Since inflammation is believed to play a key role in AD development, we sought to investigate here the in vivo homotaurine effect on inflammatory response in patients at the earliest stages of AD, i.e., suffering from amnestic mild cognitive impairment (aMCI). Thus, the present study aims to evaluate the effects of homotaurine supplementation on cytokine serum levels and memory performances in MCI patients. Neuropsychological, clinical and cytokine assessment was performed at baseline (T0) and after 1 year (T12) of homotaurine supplementation in 20 patients categorized as carriers (n = 9) or no carriers (n = 11) of the ε4 allele of the apolipoprotein E (APOE) gene, the strongest genetic risk factor for AD. The serum levels of the pro-inflammatory mediators Interleukin (IL) 1ß, Tumor necrosis factor-alpha (TNFα), IL-6 and IL-18, contextually with the anti-inflammatory molecules IL-18 binding protein (IL-18BP) and Transforming growth factor-beta (TGFß), were analyzed to explore significant differences in the inflammatory status between T0 and T12 in the two APOE variant carrier groups. No significant differences over time were observed in patients as for most cytokines, except for IL-18. Following homotaurine supplementation, patients carrying the APOEε4 allele showed a significant decrease in IL-18 (both in its total and IL-18BP unbound forms), in turn associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI may have a positive consequence on episodic memory loss due, at least in part, to homotaurine anti-inflammatory effects. This study strongly suggests that future research should focus on exploring the mechanisms by which homotaurine controls brain inflammation during AD progression.