Serum miR-34a-5p, miR-103a-3p, and miR-376a-3p as possible biomarkers of conversion from relapsing-remitting to secondary progressive multiple sclerosis.

Relapsing-remitting (RR) Multiple Sclerosis (MS) is the most common form of the disease; RRMS patients can maintain their clinical phenotype throughout life or can develop a secondary progressive (SP) course over time. We investigated whether circulating miRNAs can predict RR-to-SPMS conversion. A serum miRNAs profile was initially analyzed in a cross-sectional study by qPCR in 16 patients (8 RRMS and 8 SPMS) (Discovery cohort). Three miRNAs, i.e. miR-34a-5p, miR-103a-3p and miR-376a-3p, were significantly up-regulated in SPMS compared to RRMS patients (p < 0.0 5). Serum concentration of the same miRNAs was subsequently analyzed in a retrospective study by ddPCR at baseline in 69 RRMS patients who did (N = 36 cSPMS) or did not (N = 33) convert into SPMS over a 10-year observation period (Study cohort). The results showed that these miRNAs were significantly increased at baseline only in those RRMS patients who converted to SPMS over time. miR-34a-5p and miR-376a-3p alone were significantly increased in cSPMS sera at the end of the 10-years period too. Serum concentration of miR-34a-5p, miR-103a-3p and miR-376a-3p is increased in RRMS patients several years before their conversion to SPMS. These miRNAs might be useful biomarkers to predict the conversion from RRMS to SPMS.

Special Issue "Epigenetics in Neurodegenerative Diseases".

Epigenetic mechanisms inducing phenotypic changes without altering the DNA genome are increasingly recognized as key factors modulating gene expression and, consequently, cell functions [...].

Evaluation of serum miRNAs expression in frail and robust subjects undergoing multicomponent exercise protocol (VIVIFRAIL).

BACKGROUND: Frailty, defined as physical performance impairment, is a common condition in older adults and can anticipate the development of sarcopenia, a geriatric syndrome characterized by loss of muscle strength and mass. microRNAs (miRNAs) are short molecules of RNA endowed with the ability to modulate gene expression; miRNAs are present in serum and are considered potential biomarkers for several diseases. Serum concentration of miR-451a, miR-93-5p, miR-155-5p, miR-421-3p, miR-425-5p, miR-495-3p and miR-744-5p was recently shown to be altered in sarcopenic patients. METHODS: We verified if a particular miRNAs pattern could be detected in frailty as well by analyzing these molecules in 50 frail and 136 robust subjects. Additionally, a subgroup of these subjects (15 frail and 30 robust) underwent a 12-week program based on a multicomponent exercise protocol (VIVIFRAIL) consisting of resistance training, gait retraining, and balance training. After the program, serum miRNAs concentration was measured again, to verify whether the physical activity had an effect on their concentration. Moreover, clinical characteristics and indicators of physical performance of all subjects were compared before and after intervention to verify the effect of the VIVIFRAIL program. RESULTS: At the end of the multicomponent exercise program, Short Physical Performance Battery (SPPB) score as well right and left handgrip (p < 0.05) were significantly increased in frail subjects; right and left handgrip significantly were increased also in robust subjects (p < 0.05). Interestingly, the variation of SPPB was significantly higher in frail compared to robust subjects (p < 0.0001). Moreover, at the end of the program, in frail compared to robust subjects: miR-451a serum concentration was significantly increased (frail: 6.59 × 104; 1.12 × 104-2.5 × 105 c/ng; robust: 2.31 × 104; 1.94 × 103-2.01 × 105 c/ng) (p < 0.05); and 2) miR-93-5p and miR-495-3p serum concentration was reduced, whereas that of miR-155-5p was significantly increased (p < 0.05 in both cases). Serum concentration of miR-93-5p and miR-495-3p was decreased, and that of miR-155-5p was increased at the end of the program in robust subjects alone, statistical significance being reached for miR-93-5p alone (p = 0.02). CONCLUSION: These results suggest that serum miR-451a should be investigated as a potential biomarker for frailty and show that the VIVIFRAIL multicomponent program modulates circulatory miRNAs expression, at least in older adults.

Inflammatory and immune marker trajectories from pregnancy to one-year post-birth.

BACKGROUND: Pregnancy is an immunomodulatory state, with reported systematic changes in inflammatory and immune activity by pregnancy stage. Published data are inconsistent as to how inflammatory and immune markers change and recover across pregnancy and the postpartum period, or the sociodemographic, health and pregnancy-related factors that could affect biomarker trajectories. The purpose of this study is to describe inflammatory and immune marker trajectories from pregnancy to a year post-birth, and to test associations with sociodemographic, health and pregnancy-related variables. METHODS: A sample of 179 pregnant women were assessed three times during pregnancy (between 8 and 36 weeks gestation) and three times during the postpartum period (between 1 and 12 months). Maternal sociodemographic characteristics, health, and pregnancy factors were obtained at study entry. Blood samples from each assessment were assayed for interleukin(IL)-6, tumor necrosis factor(TNF)α, IL-8, IL-10, and interferon(IFN)γ. Multilevel modelling was used to characterize biomarker trajectories and associations with sociodemographic and health variables. RESULTS: Distinct trajectories over time emerged for each biomarker. Male pregnancies were associated with higher TNFα, IL-10, and IFNγ; higher pre-pregnancy BMI was associated with higher IL-6 and IFNγ. Nulliparity was associated with greater increases in IL-6 and TNFα. CONCLUSIONS: Patterns observed for inflammatory and immune markers from pregnancy to a year postpartum support the hypothesis that the maternal immune system changes systematically across pregnancy and through an extended postpartum period. Parity, pre-pregnancy BMI and child sex are associated with inflammatory marker patterns over time. These results contribute to our understanding of how immune system activity changes from pregnancy to the post-birth period, and the factors that could affect those changes.

Sarcopenia associates with SNAP-25 SNPs and a miRNAs profile which is modulated by structured rehabilitation treatment.

BACKGROUND: Sarcopenia is a loss of muscle mass and strength causing disability, morbidity, and mortality in older adults, which is characterized by alterations of the neuromuscular junctions (NMJs). SNAP-25 is essential for the maintenance of NMJ integrity, and the expression of this protein was shown to be modulated by the SNAP-25 rs363050 polymorphism and by a number of miRNAs. METHODS: We analysed these parameters in a cohort of sarcopenic patients undergoing structured rehabilitation. The rs363050 genotype frequency distribution was analyzed in 177 sarcopenic patients and 181 healthy controls (HC). The concentration of seven miRNAs (miR-451a, miR-425-5p, miR155-5p, miR-421-3p, miR-495-3p, miR-744-5p and miR-93-5p), identified by mouse brain miRNome analysis to be differentially expressed in wild type compared to SNAP-25± heterozygous mice, was analyzed as well by droplet digital PCR (ddPCR) in a subgroup of severe sarcopenic patients undergoing rehabilitation. RESULTS: The SNAP-25 rs363050 AA genotype was significantly more common in sarcopenic patients compared to HC (pc = 0.01); miR-451a was significantly up-regulated in these patients before rehabilitation. Rehabilitation modified miRNAs expression, as miR-155-5p, miR-421-3p, miR-451a, miR-425-5p, miR-744-5p and miR-93-5p expression was significantly up-regulated (p < 0.01), whereas that of miR-495-3p was significantly down-regulated (p < 0.001) by rehabilitation. Notably, rehabilitation-associated improvement of the muscle-skeletal SPPB score was significantly associated with the reduction of miR-451a expression. CONCLUSION: These results support the hypothesis of a role for SNAP-25 in sarcopenia and suggest SNAP-25-associated miRNAs as circulatory biomarkers of rehabilitative outcome for sarcopenia.

Relation between FCGRIIB rs1050501 and HSV-1 specific IgG antibodies in Alzheimer's disease.

BACKGROUND: Alzheimer's Disease (AD) is a chronic neurodegenerative disorder characterized by extracellular plaques, intracellular neurofibrillary tangles and neuronal loss in the central nervous system (CNS). Pathogens are suspected to have a role in the development of AD; herpes simplex virus type 1 (HSV-1), in particular, is suggested to be a risk factor for the disease. The gamma receptor for the Fc portion of IgG molecules (FCGRs) plays a crucial role in regulating immune responses, and among FCGRs, FCGRIIB is endowed with an inhibitory function. Notably, the rs1050501 polymorphism of FCGRIIB gene associates with autoimmune diseases and with neuronal uptake and interneuronal accumulation of amyloid beta in animal AD models. METHODS: Genotype and allelic distribution of ApoE4 and FCGRIIB rs1050501 were evaluated in a case-control population of 225 AD patients, 93 MCI individuals and 201 sex and age matched healthy controls (HC). HSV-1 total IgG titers and IgG subclasses were detected and quantified in a subgroup of the main study population by ELISA. RESULTS: Genotype and allelic distribution of FCGRIIB was comparable in the study population. HSV-1-specific antibody titers were significantly higher in AD and MCI compared to HC (p < 0.01 for both); IgG3 titers, in particular, were increased in MCI compared to AD (p = 0.04). Analyses of possible correlations between the FCGRIIB rs1050501 genotype polymorphism and IgG subclasses showed that the presence of IgG3 was more frequent in MCI carrying the FCGRIIB TT (94.1%) compared to those carrying the CT genotype (63.6%) (p = 0.03). CONCLUSION: Results herein show an association between humoral immune response against HSV-1 and FCGRIIB rs1050501 genetic variation in the first stage of the disease.

COS-7 cells are a cellular model to monitor polyomavirus JC miR-J1-5p expression.

Polyomavirus JC (JCPyV) is a ubiquitous human neurotropic virus that can cause progressive multifocal leukoencephalopathy (PML), sometimes as a consequence of drug treatment for disabling diseases, including Multiple Sclerosis. JCPyV expresses microRNAs (miRNAs), and in particular miR-J1-5p, but at now we have limited knowledge regarding this aspect. In the present study the expression of JCPyV miR-J1-5p was measured in infected COS-7, to verify if and when this miRNA is expressed in a cell model of JCPyV-MAD-4 strain infection. Results showed that miR-J1-5p expression was relatively constant inside the cells from 11 days to 35 days after infection (mean: 4.13 × 105 copies/µg), and became measurable in supernatants 18 days after infection (mean: 7.20 × 104 copies/µl). miR-J1-5p expression in supernatants peaked (3.76 × 105 copies/µl) 25 days after infection and started to decrease 32 days after infection (7.20 × 104 copies/µl). These data show that COS-7 cells, already used as model for JCPyV replication cycle, can be also utilized to study JCPyV miRNAs expression, potentially opening new research avenues for diseases in which current therapeutic approaches could result in severe adverse effects (e.g. Natalizumab-associated JCPyV reactivation in Multiple Sclerosis patients). In these situations monitoring of miR-J1-5p may shed light on the mechanisms of virus reactivation and may help the clarification of the mechanisms responsible for such severe side effects.

Herpes simplex virus-1 (HSV-1) infection induces a potent but ineffective IFN-λ production in immune cells of AD and PD patients.

BACKGROUND: The sequential activation of immediate early (IE), early (E) and late (L) genes is required to allow productive herpes simplex virus type 1 (HSV-1) infection. Several evidences suggest that, together with inflammation, an immunological response incapable to counteract HSV-1 reactivation plays a role in the pathogenesis of Alzheimer's (AD) and Parkinson's (PD) diseases. IFN-lambda (IFN-λ), a cytokine endowed with a robust antiviral activity, contains HSV-1 reactivation. HSV-1-induced IFN-λ, IL-10 and IL-1ß as well as the expression of viral IE, E and L genes were analyzed in vitro in peripheral blood mononuclear cells (PBMC) of AD and PD patients as well as of healthy controls (HC). METHODS: PBMC of AD, PD and HC were in vitro infected with one multiplicity of infection (1 MOI) HSV-1. IE, E, and L viral genes transcription as well as IFN-λ, IL-10 and IL-1ß production were analyzed. RESULTS: In HSV-1-infected cells of AD and PD patients compared to HC: (1) transcription of IE (ICP0, ICP27) genes was reduced whereas that of E (UL41, UL29) and L (UL48, LAT) genes was increased; (2) IFN-λ mRNA expression was increased. IL-1ß was augmented and IL-10 was reduced in unstimulated cells of AD and PD compared to HC; HSV-1 infection significantly increased IL-10 production in HC alone. CONCLUSIONS: Data herein show that a proinflammatory condition is present in AD and PD, in whom attempts to obstacle viral replication via an initial, possibly more potent IFN-λ-mediated control of IE viral genes is unsuccessful.

The PILRA G78R Variant Correlates with Higher HSV-1-Specific IgG Titers in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive decline in cognitive performance; Mild Cognitive Impairment (MCI) is instead an objective decline in cognitive performance that does not reach pathology. Paired immunoglobulin-like type 2 receptor alpha (PILRA) is a cell surface inhibitory receptor that was recently suggested to be involved in AD pathogenesis. In particular, the arginine-to-glycine substitution in position 78 (R78, rs1859788) was shown to be protective against AD. Herpes simplex virus type 1 (HSV-1) infection is suspected as well to be involved in AD. Interestingly, HSV-1 uses PILRA to infect cells, and HSV-1 infects more efficiently PIRLA G78 compared to R78 macrophages. We analyzed PILRA rs1859788 polymorphism and HSV-1 humoral immune responses in AD (n = 61) and MCI patients (n = 48), and in sex and age matched healthy controls (HC; n = 57). The rs1859788 PILRA genotype distribution was similar among AD, MCI and HC; HSV-1 antibody (Ab) titers were increased in AD and MCI compared to HC (p < 0.05 for both comparisons). Notably, HSV-1-specific IgG1 were significantly increased in AD patients carrying PILRA R78 rs1859788 AA than in those carrying G78 AG or GG (p = 0.01 for both comparisons), and the lowest titers of HSV-1-specific IgG1 were observed in rs1859788 GG AD. HSV-1 IgG are increased in AD patients with the protective R78 PILRA genotype. Because in AD patients brain atrophy is inversely correlated with HSV-1-specific IgG titers, results herein suggest a possible link between two important genetic and infective factors suspected to be involved in AD pathogenesis.

A simple and universal enzyme-free approach for the detection of multiple microRNAs using a single nanostructured enhancer of surface plasmon resonance imaging.

Here we describe a simple approach for the simultaneous detection of multiple microRNAs (miRNAs) using a single nanostructured reagent as surface plasmon resonance imaging (SPRi) enhancer and without using enzymatic reactions, sequence specific enhancers or multiple enhancing steps as normally reported in similar studies. The strategy involves the preparation and optimisation of neutravidin-coated gold nanospheres (nGNSs) functionalised with a previously biotinylated antibody (Ab) against DNA/RNA hybrids. The Ab guarantees the recognition of any miRNA sequence adsorbed on a surface properly functionalised with different DNA probes; at the same time, gold nanoparticles permit to detect this interaction, thus producing enough SPRi signal even at a low ligand concentration. After a careful optimisation of the nanoenhancer and after its characterisation, the final assay allowed the simultaneous detection of four miRNAs with a limit of detection (LOD) of up to 0.5 pM (equal to 275 attomoles in 500 µL) by performing a single enhancing injection. The proposed strategy shows good signal specificity and permits to discriminate wild-type, single- and triple-mutated sequences much better than non-enhanced SPRi. Finally, the method works properly in complex samples (total RNA extracted from blood) as demonstrated by the detection of four miRNAs potentially related to multiple sclerosis used as case study. This proof-of-concept study confirms that the approach provides the possibility to detect a theoretically unlimited number of miRNAs using a simple protocol and an easily prepared enhancing reagent, and may further facilitate the development of affordable multiplexing miRNA screening for clinical purposes.

HLA alleles modulate EBV viral load in multiple sclerosis.

BACKGROUND: The etiopathology of multiple sclerosis (MS) is believed to include genetic and environmental factors. Human leukocyte antigen (HLA) alleles, in particular,  are associated with disease susceptibility, whereas Epstein Barr Virus (EBV) infection has long been suspected to play a role in disease pathogenesis. The aim of the present study is to evaluate correlations between HLA alleles and EBV infection in MS. METHODS: HLA alleles, EBV viral load (VL) and serum anti-EBV antibody titers were evaluated in EBV-seropositive MS patients (N = 117) and age- and sex-matched healthy controls (HC; N = 89). RESULTS: Significantly higher DNA viral loads (p = 0.048) and EBNA-1 antibody titer (p = 0.0004) were seen in MS compared to HC. EBV VL was higher in HLA-B*07+ (p = 0.02) and HLA-DRB1*15+ (p = 0.02) MS patients, whereas it was lower in HLA-A*02+ (p = 0.04) subjects. EBV VL was highest in HLA-A*02-/B*07+/DRB1*15+ patients and lowest in HLA-A*A02+/B*07-/DRB1*15- individuals (p < 0.0001). HLA-B*07 resulted the most associated allele to EBV VL after multiple regression analysis considering altogether the three alleles, (p = 0.0001). No differences were observed in anti-EBV antibody titers in relationship with HLA distribution. CONCLUSIONS: Host HLA-B*07 allele influence EBV VL in MS. As HLA-class I molecules present antigens to T lymphocytes and initiate immune response against viruses, these results could support a role for EBV in MS.

NCAM1 is the Target of miRNA-572: Validation in the Human Oligodendroglial Cell Line.

The neural cell adhesion molecule 1 (NCAM1) is a fundamental protein in cell-cell interaction and in cellular developmental processes, and its dysregulation is involved in a number of diseases including multiple sclerosis. Studies in rats suggest that the modulation of NCAM1 expression is regulated by miRNA-572, but no data are available confirming such interaction in the human system. We analyzed whether this is the case using a human oligodendroglial cell line (MO3.13). MO3.13 cells were transfected with miRNA-572 mimic and inhibitor separately; NCAM1 mRNA and protein expression levels were analyzed at different time points after transfection. Results indicated that NCAM1 expression is increased after transfection with miRNA-572 inhibitor, whereas it is decreased after transfection with the mimic (p < 0.005). The interaction between NCAM1 and miRNA-572 was subsequently confirmed in a Vero cell line that does not express NCAM1, by luciferase assay after transfection with NCAM1. These results confirm that miRNA-572 regulates NCAM1 and for the first time demonstrate that this interaction regulates NCAM1 expression in human cells. Data herein also support the hypothesis that miRNA-572 is involved in diseases associated with NCAM1 deregulation, suggesting its possible use as a biomarker in these diseases.

Poor sleep quality increases symptoms of depression and anxiety in postpartum women.

This study evaluated the relationship between sleep quality and symptoms of depression and anxiety in women studied in pregnancy and postpartum. Scores on standardized measures of sleep (PSQI) at 6 months postpartum, and symptoms of anxiety and depression (OASIS, the PHQ9, and EPDS) were assessed by structured interviews in 116 women in pregnancy and/or postpartum. Poor sleep quality was significantly associated with greater symptoms of depression and anxiety. Women who had significantly higher OASIS (anxiety) scores (ß = .530, p < .001), PHQ9 (depression) scores (ß = .496, p < .001), and EPDS (postpartum depression and anxiety) scores (ß = .585, p < .001) also had elevated total PSQI scores after adjustment for covariates, including prenatal depression and anxiety scores. Though inferences about causality are not feasible, these results support emerging research showing sleep quality is a risk factor for negative maternal affect in the postpartum period. Assessment of maternal sleep hygiene is worth consideration as a component of identifying women at risk for postpartum depression and anxiety.

High avidity HSV-1 antibodies correlate with absence of amnestic Mild Cognitive Impairment conversion to Alzheimer's disease.

Amnestic Mild Cognitive Impairment (aMCI) is an alteration in cognitive abilities that can progress to Alzheimer's disease (AD), a condition in which herpes simplex type 1 (HSV-1) infection might play a pathogenetic role. Prognostic indexes capable of predicting aMCI conversion to AD are only partially understood. The objective of the present work is to verify whether HSV-1 immune responses is involved in conversion of aMCI to AD and correlate with grey matter brain morphometry. Two homogeneous groups of individuals who did or did not convert to AD over a 24-months period were selected after retrospective analysis of a cohort of patients with a diagnosis of aMCI. The selection of subjects was based on: a) clinical follow-up; b) neurocognitive evaluation at baseline and after 24months; c) availability of serum and DNA samples at baseline. 36 aMCI individuals, 21 of whom did (aMCI-converters) and 15 of whom did not (aMCI-non-converters) convert to AD, were included in the study. HSV-1 antibody (Ab) titers, avidity index and APOE genotyping were performed in all the enrolled individuals at baseline. Brain magnetic resonance imaging (MRI) by 1.5T scanner results at baseline were available as well in most (29/36) of these individuals. HSV-1-specific Ab titers were increased at baseline in aMCI-non-converters, and the avidity of these Ab was significantly higher in aMCI-non-converter compared to aMCI-converter (p=0.0018). Receiver operating characteristics analysis showed that HSV-1 avidity had a predictive value in distinguishing between aMCI-non-converters and aMCI-converters (p<0.0001). Notably, a positive correlation was detected as well between HSV-1 antibody titers and MRI-evaluated cortical volumes in the left hippocampus and amigdala (pcorr<0.05). In conclusion, stronger HSV-1-specific humoral responses associate with protection against AD conversion and better-preserved cortical volumes. These results reinforce the hypothesis for a role for HSV-1 in the pathogenesis of AD.

Whole-Genome Sequencing Identifies STAT4 as a Putative Susceptibility Gene in Classic Kaposi Sarcoma.

BACKGROUND: Classic Kaposi sarcoma (cKS) is an inflammatory tumor caused by human herpesvirus 8 (HHV-8) commonly observed in elderly men of Mediterranean origin. We studied a Finnish family of 5 affected individuals in 2 generations. Except for atypical mycobacterial infection of the index case, the affected individuals did not have notable histories of infection. METHODS: We performed genome and exome sequencing and mapped shared chromosomal regions to identify genetic predisposition in the family. RESULTS: We identified 12 protein-coding candidate variants that segregated in the 3 affected cousins from whom we had samples. The affected mother of the index case was an obligatory carrier. Among the 12 candidates was a rare heterozygous substitution rs141331848 (c.1337C>T, p.Thr446Ile) in the DNA-binding domain of STAT4. The variant was not present in 242 Finnish control genomes or 180 additional regional controls. Activated T-helper cells from the HHV-8-negative variant carriers showed reduced interferon γ production, compared with age and sex matched wild-type individuals. We screened STAT4 in additional 18 familial KS cases and the variant site from 56 sporadic KS cases but detected no pathogenic mutations. CONCLUSIONS: Our data suggest that STAT4 is a potential cKS-predisposition gene, but further functional and genetic validation is needed.

MicroRNA-572 expression in multiple sclerosis patients with different patterns of clinical progression.

BACKGROUND: Demyelination and failure of remyelination are core mechanisms in the pathogenesis of multiple sclerosis (MS); the factor(s) modulating these processes are still mostly unknown. MicroRNA 572 (miR-572) is deregulated in MS and is suggested to targets neural cell adhesion molecule (NCAM), a glycoprotein involved in CNS reparative mechanisms. The aim of this study is to analyze miR-572 in patients with different clinical phenotypes of MS. METHODS: qPCR quantification of miR-572 isolated from serum was performed in 16 primary progressive (PP), 15 secondary progressive (SP), 31 relapsing remitting (RR) MS patients and 15 sex-and age-matched healthy controls. RESULTS: miR-572 expression was reduced overall in MS patients (p < 0.05) compared to HC; this miRNA was significantly upregulated in SPMS and in RRMS during disease relapse, whereas it was downregulated in PPMS and in quiescent phases of RRMS. miR-572 expression correlated with EDSS scores (RSp = 0.491; p < 0.05) independently of the clinical phenotype. The results suggest that this miRNA might be a tool that helps distinguishing between PPMS and SPMS and between relapsing and remitting phases in RRMS. CONCLUSIONS: Evaluation of miR-572 may serve as a non-invasive biomarker for remyelination.

EBV and multiple sclerosis: expression of LMP2A in MS patients.

Several evidences, including increased serum titers of Epstein-Barr virus (EBV)-specific antibodies and the presence of EBV DNA in brain of patients suggest a possible role of this virus in the pathogenesis of Multiple Sclerosis (MS), a chronic neurodegenerative disease with an unknown etiopathology. Aim of the present study is to verify if the expression of LMP2A and EBNA-1, two EBV genes, is altered in MS patients. EBV viral load, LMP2A and EBNA-1 gene expression and EBNA-1 antibodies titers were evaluated in blood of EBV-seropositive MS patients (n = 57; 31 relapsing remitting -RRMS- and 26 progressive -PMS-patients) and age- and sex-matched healthy controls (HC, n = 49). Results showed that EBNA-1 and VCA antibodies titers are significantly augmented in MS patients compared to HC (p < 0.05 for both antibodies); detection of EBV DNA was more frequent as well in MS patients compared to HC, although without reaching statistical significance. Regarding viral gene expression, LMP2A was significantly more frequently detected and more expressed in MS patients compared to HC (p < 0.005) whereas no differences were observed for EBNA-1. Considering patients alone, EBNA-1 was significantly more frequent in PMS compared to RRMS (p < 0.05), whereas no differences were observed for LMP2A. Increased expression of the LMP2A latency-associated gene in MS patients supports the hypothesis that EBV plays a role in disease etiopathology.

Prenatal mood and anxiety disorders and associated cytokine changes.

BACKGROUND: We examined whether women with prenatal mood and anxiety disorders would exhibit differential pro- and anti-inflammatory marker trajectories during the prenatal and postpartum periods compared to women without these disorders. METHODS: Approximately 179 pregnant women participated in a longitudinal study conducted in two urban areas. Blood samples for inflammatory markers were collected at six study visits. The Structured Clinical Interview for the DSM-IV (SCID) was administered to participants scoring above cutoffs on anxiety and depression. Pregnant women with SCID Axis I diagnoses of mood and/or anxiety disorders were compared to other participants on inflammatory markers. Multilevel modeling tested associations between SCID diagnoses and within-person interleukin (IL)6 and IL10 trajectories. RESULTS: Prenatal SCID diagnoses were associated with linear, quadratic and cubic change in IL6 from prenatal to postpartum timepoints. Women with a prenatal SCID diagnosis had steeper decreases and increases in IL6 during prenatal and postpartum periods. SCID diagnoses were associated with lower IL10 in mid-pregnancy to postpartum (b = -0.078, SE = 0.019; p = .015). LIMITATIONS: Future studies would benefit from a larger sample size and a larger number of participants with SCID diagnoses. Future research should also examine whether different prenatal Axis 1 diagnoses are associated with different patterns of immune response in pregnancy. CONCLUSIONS: Pregnant women with prenatal mood and anxiety disorders had greater fluctuations in IL6 across prenatal and postpartum periods and lower IL10 through pregnancy and postpartum. They may have different proinflammatory states that remain after birth without a reciprocal anti-inflammatory response.

Biomarkers of neural integrity and immunoglobulin genes influence neurodegeneration in Alzheimer's disease.

Compelling evidence has been presented in favor of herpes simplex virus type 1 (HSV1) being one of the causative agents of Alzheimer's disease (AD). The success of HSV1 as a pathogen relates to its sophisticated strategies to evade host immunosurveillance. One strategy involves encoding a decoy Fcγ receptor (FcγR) that thwarts the Fcγ-mediated effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), a potent host immunosurveillance mechanism against virally infected cells. The decoy FcγR binds to antibodies of all IgG subclasses, except IgG3; therefore, IgG3 would be expected to play an important role in viral clearance by neutralization and ADCC, and thus contribute to protection from HSV1-spurred diseases. Previous studies have shown significant association between anti-HSV1 IgG3 antibodies and cortical thinning of the areas of the brain typically altered in AD and also targeted by HSV1. The aim of the present investigation was to determine whether GM (γ marker) 5 and GM 21 allotypes, hereditary allelic determinants expressed on IgG3, together with brain biomarkers of neural integrity, contributed to neurodegeneration-as measured by mini-mental state examination (MMSE) score-in patients with AD. Multiple regression analyses showed that the homozygous GM 5/5 genotype, preserved right hippocampus, and right insula thickness were associated with higher MMSE scores (p < 0.001), whereas the opposite pattern and GM 5/21 genotype were associated with worse clinical profiles. Influence of GM 5/21-expressing IgG3 antibodies on the ADCC of HSV1-infected neurons could, at least partially, explain these results.

The role of microRNAs in understanding sex-based differences in Alzheimer's disease.

BACKGROUND: The incidence of Alzheimer's disease (AD)-the most frequent cause of dementia-is expected to increase as life expectancies rise across the globe. While sex-based differences in AD have previously been described, there remain uncertainties regarding any association between sex and disease-associated molecular mechanisms. Studying sex-specific expression profiles of regulatory factors such as microRNAs (miRNAs) could contribute to more accurate disease diagnosis and treatment. METHODS: A systematic review identified six studies of microRNA expression in AD patients that incorporated information regarding the biological sex of samples in the Gene Expression Omnibus repository. A differential microRNA expression analysis was performed, considering disease status and patient sex. Subsequently, results were integrated within a meta-analysis methodology, with a functional enrichment of meta-analysis results establishing an association between altered miRNA expression and relevant Gene Ontology terms. RESULTS: Meta-analyses of miRNA expression profiles in blood samples revealed the alteration of sixteen miRNAs in female and 22 miRNAs in male AD patients. We discovered nine miRNAs commonly overexpressed in both sexes, suggesting a shared miRNA dysregulation profile. Functional enrichment results based on miRNA profiles revealed sex-based differences in biological processes; most affected processes related to ubiquitination, regulation of different kinase activities, and apoptotic processes in males, but RNA splicing and translation in females. Meta-analyses of miRNA expression profiles in brain samples revealed the alteration of six miRNAs in female and four miRNAs in male AD patients. We observed a single underexpressed miRNA in female and male AD patients (hsa-miR-767-5p); however, the functional enrichment analysis for brain samples did not reveal any specifically affected biological process. CONCLUSIONS: Sex-specific meta-analyses supported the detection of differentially expressed miRNAs in female and male AD patients, highlighting the relevance of sex-based information in biomedical data. Further studies on miRNA regulation in AD patients should meet the criteria for comparability and standardization of information.

Alzheimer's disease (AD)­a neurodegenerative disease mainly affecting older patients­is characterized by cognitive deterioration, memory loss, and progressive incapacitation in daily activities. While AD affects almost twice as many females as males, and cognitive deterioration and brain atrophy develop more rapidly in females, the biological causes of these differences remain poorly understood. MicroRNAs (miRNAs) regulate gene expression and impact a wide variety of biological processes; therefore, studying the differential expression of miRNAs in female and male AD patients could contribute to a better understanding of the disease. We reviewed studies of miRNA expression in female and male AD patients and integrated results using a meta-analysis methodology and then identified those genes regulated by the altered miRNAs to establish an association with biological processes. We found 16 (females) and 22 (males) miRNAs altered in the blood of AD patients. Functional enrichment revealed sex-based differences in the affected altered biological processes­protein modification and degradation and cell death in male AD patients and RNA processing in female AD patients. A similar analysis in the brains of AD patients revealed six (females) and four (males) miRNAs with altered expression; however, our analysis failed to highlight any specifically altered biological processes. Overall, we highlight the sex-based differential expression of miRNAs (and biological processes affected) in the blood and brain of AD patients.