The PINK1 p.Asn521Thr Variant Is Associated with Earlier Disease Onset in GRN/C9orf72 Frontotemporal Lobar Degeneration.

Genetic frontotemporal lobar degeneration (FTLD) is characterized by heterogeneous phenotypic expression, with a disease onset highly variable even in patients carrying the same mutation. Herein we investigated if variants in lysosomal genes modulate the age of onset both in FTLD due to GRN null mutations and C9orf72 expansion. In a total of 127 subjects (n = 74 GRN mutations and n = 53 C9orf72 expansion carriers), we performed targeted sequencing of the top 98 genes belonging to the lysosomal pathway, selected based on their high expression in multiple brain regions. We described an earlier disease onset in GRN/C9orf72 pedigrees in subjects carrying the p.Asn521Thr variant (rs1043424) in PTEN-induced kinase 1 (PINK1), a gene that is already known to be involved in neurodegenerative diseases. We found that: (i) the PINK1 rs1043424 C allele is significantly associated with the age of onset; (ii) every risk C allele increases hazard by 2.11%; (iii) the estimated median age of onset in homozygous risk allele carriers is 10-12 years earlier than heterozygous/wild type homozygous subjects. A replication study in GRN/C9orf72 negative FTLD patients confirmed that the rs1043424 C allele was associated with earlier disease onset (-5.5 years in CC versus A carriers). Understanding the potential mechanisms behind the observed modulating effect of the PINK1 gene in FTLD might prove critical for identifying biomarkers and/or designing drugs to modify the age of onset, especially in GRN/C9orf72-driven disease.

Intermediate lengths of the C9ORF72 hexanucleotide repeat expansion may synergistically contribute to attention deficit hyperactivity disorder in child and his father: case report.

We have summarized the abstract section as follows: "We report a son and his father affected by Attention Deficit Hyperactivity Disorder (ADHD). They belonged to a larger cohort (116 ADHD children, 20 related parents, 77 controls) wholly genotyped forC9ORF72 expansion. Ten ADHD susceptibility genes were further investigated in the family. We revealed that son and father shared an intermediateC9ORF72 expansion and common variants inCDH23, ITGAE and MTRR. Bioinformatics highlighted aC9ORF72-MTRR interaction. This case-report underlines that in relatives with ADHD, carrying variants in ADHD susceptibility genes, the intermediateC9ORF72 repeats might have a potentially pathogenetic synergistic effect, supporting the multifactorial polygenic aetiopathogenetic profile of disease".

Investigating the Endo-Lysosomal System in Major Neurocognitive Disorders Due to Alzheimer's Disease, Frontotemporal Lobar Degeneration and Lewy Body Disease: Evidence for SORL1 as a Cross-Disease Gene.

Dysfunctions in the endo-lysosomal system have been hypothesized to underlie neurodegeneration in major neurocognitive disorders due to Alzheimer's disease (AD), Frontotemporal Lobar Degeneration (FTLD), and Lewy body disease (DLB). The aim of this study is to investigate whether these diseases share genetic variability in the endo-lysosomal pathway. In AD, DLB, and FTLD patients and in controls (948 subjects), we performed a targeted sequencing of the top 50 genes belonging to the endo-lysosomal pathway. Genetic analyses revealed (i) four previously reported disease-associated variants in the SORL1 (p.N1246K, p.N371T, p.D2065V) and DNAJC6 genes (p.M133L) in AD, FTLD, and DLB, extending the previous knowledge attesting SORL1 and DNAJC6 as AD- and PD-related genes, respectively; (ii) three predicted null variants in AD patients in the SORL1 (p.R985X in early onset familial AD, p.R1207X) and PPT1 (p.R48X in early onset familial AD) genes, where loss of function is a known disease mechanism. A single variant and gene burden analysis revealed some nominally significant results of potential interest for SORL1 and DNAJC6 genes. Our data highlight that genes controlling key endo-lysosomal processes (i.e., protein sorting/transport, clathrin-coated vesicle uncoating, lysosomal enzymatic activity regulation) might be involved in AD, FTLD and DLB pathogenesis, thus suggesting an etiological link behind these diseases.

Genetic determinants of circulating VEGF levels in major depressive disorder and electroconvulsive therapy response.

Alterations in peripheral vascular endothelial growth factor (VEGF) levels were observed in major depressive disorder and relative treatments and were shown to be influenced by genetic variants. The study objective was to explore, at a genome-wide level, possible interplaying effects between the genetic background and major depressive disorder in regulating VEGF levels. Moreover, we aimed to investigate the association between these variants and response to electroconvulsive therapy. A genome-wide association study was carried out both on controls and patients with major depressive disorder (n = 145; n = 121) in correlation with serum VEGF levels determined by ELISA. Five SNPs not included in SNP arrays were additionally genotyped. Seventy-one patients with treatment-resistant depression underwent electroconvulsive therapy and were evaluated as responders/nonresponders. An association between VEGF levels and a locus in 6p21.1, downstream the VEGF gene, was evidenced both in controls (best SNP: FDR-corrected p = 2.4 × 10-5 ) and in patients with major depressive disorder (best SNP: FDR-corrected p = 2.6 × 10-3 ). The alleles associated with lower VEGF concentrations in patients were also associated with nonresponse to electroconvulsive therapy (p = .01). These results confirm a role of SNPs in 6p21.1 locus as major influencers of circulating VEGF levels also in patients affected by major depressive disorder and indicate a possible implication in response to electroconvulsive therapy.

Association study between HTR2A rs6313 polymorphism and early response to risperidone and olanzapine in schizophrenia patients.

Antipsychotic drugs are the preferred choice for schizophrenia treatment; however, response is highly variable. In the context of the search for predictors of antipsychotic treatment effectiveness, the evaluation of response within 2 weeks has been indicated to predict long-term outcome. Moreover, a focus on symptomatological domains could be helpful to better characterize antipsychotic response, identifying more specific predictors. Pharmacogenetic studies have indicated a role for rs6313 in the serotonin receptor gene HTR2A in affecting response to antipsychotics, with heterogeneous results. With the aim to test for the first time the application of a dimensional approach for the evaluation of early response, we carried out a genetic association study between rs6313 and antipsychotic response in two groups of schizophrenia patients in monotherapy with risperidone (n = 121) and olanzapine (n = 100). Patients were evaluated at the baseline and after 1 and 2 weeks of treatment. When comparing early responders versus early nonresponders, no association was detected for the two drugs separately, whereas by taking into consideration the two drugs together it was observed that carriers of the T allele had a higher response probability compared to noncarriers. Considering 2-week improvements, changes in PANSS total scores, subscores and in PANSS Emsley's symptomatological dimensions were associated with rs6313 for both risperidone and olanzapine. Moreover, the repeated measures analysis indicated an association of rs6313 with the disorganized thought dimension for risperidone, and with the depressive and anxiety dimensions for olanzapine. These data add support to the hypothesis that the HTR2A gene is involved in antipsychotic treatment outcome.

The Missing Heritability of Sporadic Frontotemporal Dementia: New Insights from Rare Variants in Neurodegenerative Candidate Genes.

Frontotemporal dementia (FTD) is a common form of dementia among early-onset cases. Several genetic factors for FTD have been revealed, but a large proportion of FTD cases still have an unidentified genetic origin. Recent studies highlighted common pathobiological mechanisms among neurodegenerative diseases. In the present study, we investigated a panel of candidate genes, previously described to be associated with FTD and/or other neurodegenerative diseases by targeted next generation sequencing (NGS). We focused our study on sporadic FTD (sFTD), devoid of disease-causing mutations in GRN, MAPT and C9orf72. Since genetic factors have a substantially higher pathogenetic contribution in early onset patients than in late onset dementia, we selected patients with early onset (<65 years). Our study revealed that, in 50% of patients, rare missense potentially pathogenetic variants in genes previously associated with Alzheimer's disease, Parkinson disease, amyotrophic lateral sclerosis and Lewy body dementia (GBA, ABCA7, PARK7, FUS, SORL1, LRRK2, ALS2), confirming genetic pleiotropy in neurodegeneration. In parallel, a synergic genetic effect on FTD is suggested by the presence of variants in five different genes in one single patient. Further studies employing genome-wide approaches might highlight pathogenic variants in novel genes that explain the still missing heritability of FTD.

A PCR-based protocol to accurately size C9orf72 intermediate-length alleles.

Although large expansions of the non-coding GGGGCC repeat in C9orf72 gene are clearly defined as pathogenic for Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD), intermediate-length expansions have also been associated with those and other neurodegenerative diseases. Intermediate-length allele sizing is complicated by intrinsic properties of current PCR-based methodologies, in that somatic mosaicism could be suspected. We designed a protocol that allows the exact sizing of intermediate-length alleles, as well as the identification of large expansions.

The role of GRIK4 gene in treatment-resistant depression.

Several lines of evidence implicate abnormalities in glutamatergic neural transmission in major depressive disorder (MDD) and treatment response. A high percentage of MDD patients do not respond adequately to antidepressants and are classified as having treatment-resistant depression (TRD). In this study we investigated five GRIK4 variants, previously associated with antidepressants response, in an Italian cohort of 247 MDD no-TRD and 380 TRD patients. We found an association between rs11218030 G allele and TRD. Moreover, significant associations between rs11218030 and rs1954787 and the presence of psychotic symptoms were observed. In conclusion, our data support the involvement of GRIK4 in TRD and in the risk of developing psychotic symptoms during depressive episodes.

Alcohol dependence and serotonin transporter functional polymorphisms 5-HTTLPR and rs25531 in an Italian population.

AIMS: The role of the serotonin transporter gene (SLC6A4) in alcohol dependence (AD) is still unclear. In this paper, we have evaluated the association of the SLC6A4 gene polymorphisms 5-HTTLPR and rs25531 in AD and assessed the polymorphic patterns both in alcoholics and in healthy people of an Italian population. METHODS: Genotyping of the 5-HTTLPR (L/S) and rs25531 (A/G) polymorphisms of the SLC6A4 gene was performed on 403 alcoholics outpatients and 427 blood donors. RESULTS: Comparing AD and control populations and taking into account statistical correction for multiple testing, we found no statistically significant differences for 5-HTTLPR (L/S) and rs25531 polymorphisms in terms of either genotypes or alleles frequencies. By univariate ANOVA, a statistically significant difference was found in the onset of AD: the mean age of onset resulted to be of 25.4 years in males in respect to 28.1 in females. In particular in males, the early AD onset was different, in a statistically significant manner, depending on the presence of at least one S or Lg allele (24.6 years) in respect to La homozygotes (27.5 years) (P = 0.03). CONCLUSIONS: These findings suggest that genetic factors contribute, together with gender and age, to the onset differences in alcohol-dependent phenotypes.

Biomarkers in the diagnosis of ADHD--promising directions.

The etiology and pathogenesis of attention-deficit/hyperactivity disorder (ADHD) are unclear and a more valid diagnosis would certainly be welcomed. Starting from the literature, we built an hypothetical pyramid representing a putative set of biomarkers where, at the top, variants in DAT1 and DRD4 genes are the best candidates for their associations to neuropsychological tasks, activation in specific brain areas, methylphenidate response and gene expression levels. Interesting data come from the noradrenergic system (norepinephrine transporter, norepinephrine, 3-methoxy-4-hydroxyphenylglycol, monoamine oxidase, neuropeptide Y) for their altered peripheral levels, their association with neuropsychological tasks, symptomatology, drugs effect and brain function. Other minor putative genetic biomarkers could be dopamine beta hydroxylase and catechol-O-methyltransferase. In the bottom, we placed endophenotype biomarkers. A more deep integration of "omics" sciences along with more accurate clinical profiles and new high-throughput computational methods will allow us to identify a better list of biomarkers useful for diagnosis and therapies.

A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats.

We assessed the geographical distribution of C9orf72 G(4) C(2) expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7-24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G(4) C(2) repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G(4) C(2) repeat, which is likely more prone to replication slippage and pathological expansion.

Schizophrenia susceptibility and NMDA-receptor mediated signalling: an association study involving 32 tagSNPs of DAO, DAOA, PPP3CC, and DTNBP1 genes.

BACKGROUND: Recent studies supported associations between four NMDA-receptor-mediated signalling genes (D-amino acid oxidase, DAO; D-amino acid oxidase activator, DAOA; protein phosphatase 3 catalytic subunit gamma isoform, PPP3CC; dystrobrevin-binding protein 1, DTNBP1) and schizophrenia susceptibility, even though with contrasting results. METHODS: In an attempt to replicate these findings for the first time in an Italian population, a panel of 32 tagSNPs was analysed in a representative case-control sample involving 879 subjects. RESULTS: An association in the allele frequency was observed for the estimated PPP3CC CAG triplotype in the SNP window rs4872499 T/C-rs11780915 A/G-rs13271367 G/A (pcorrect = 0.001). Similarly, the clustered genotype frequencies of the estimated/phased CAG triplotype differed between cases and controls (p = 0.004), with the carriers having a higher frequency in the control population (p = 0.002, odd ratio OR = 0.59, 95% confident interval CI: 0.43-0.82).Following the phenotypic dissection strategy, the analysis of single SNPs evidenced a protective effect in males of rs11780915 and rs13271367 in PPP3CC gene (pcorrect = 0.02, pcorrect = 0.04 respectively). Moreover the estimated/phased GT diplotype (rs2070586A/G-rs3741775G/T) carriers of the DAO gene were more highly represented in female controls (p = 0.017, OR = 0.58, 95% CI: 0.37-0.90), as were the estimated/phased CAG triplotype carriers of the PPP3CC gene in females (p = 0.01, OR = 0.53, 95% CI: 0.32-0.87). In addition, we performed an interaction analysis, and a 66% (p = 0.003, OR = 0.34, 95% CI: 0.17-0.70) lower risk of developing schizophrenia for female (CAG + GT) carriers versus non-CAG or -GT carriers was observed. For DTNBP1, we found a protective effect in males for the rs6459409 (pcorrect = 0.02) and the estimated/phased CT diplotype (rs6459409-rs9476886) carriers (p = 3x10-4, OR = 0.46, 95% CI: 0.30-0.70).In relation to diagnostic subtypes, the estimated/phased DAO GT diplotype and PPP3CC CAG triplotype female carriers were found to show relative risk ratio (RRR) values of 0.52 and 0.54 lower risk for a paranoid phenotype respectively. CONCLUSIONS: Although the results are preliminary and needed replication in a larger sample, this study suggests that NMDA receptor-mediated signalling genes (DAO, PPP3CC, DTNBP1) might be involved in schizophrenia pathogenic mechanisms related to gender.

Atypical presentation of a novel Presenilin 1 R377W mutation: sporadic, late-onset Alzheimer disease with epilepsy and frontotemporal atrophy.

Mutations within Presenilin 1 (PSEN1) represent the most common cause of monogenic Alzheimer Disease (AD). The clinical phenotype is highly variable, even if early onset disease with an autosomal dominant pattern of inheritance and presenting memory deficits usually occur. In the present work, we described the case of a late-onset AD patient, without any positive family history for dementia, and associated with seizures and behavioural symptoms. Structural and functional neuroimaging showed frontotemporal changes without posterior biparietal brain abnormalities. Cerebrospinal analysis was consistent with AD pattern, with decreased Aß42 and increased Tau and phospho-Tau. A novel pathogenetic mutation within PSEN1 gene was detected within exon 8, leading to a substitution from arginine to tryptophan (AGG > TGG: R377W), affecting a splice junction and protein function. The case herein reported further confirms the heterogeneity of PSEN1 mutations and the need to take into account genetic screening in those cases with atypical presentation.

A genome-wide investigation of SNPs and CNVs in schizophrenia.

We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater "load" of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.

The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence.

Cellular senescence is an irreversible state of cell cycle arrest occurring in response to stressful stimuli, such as telomere attrition, DNA damage, reactive oxygen species, and oncogenic proteins. Although beneficial and protective in several physiological processes, an excessive senescent cell burden has been involved in various pathological conditions including aging, tissue dysfunction and chronic diseases. Oxidative stress (OS) can drive senescence due to a loss of balance between pro-oxidant stimuli and antioxidant defences. Therefore, the identification and characterization of antioxidant compounds capable of preventing or counteracting the senescent phenotype is of major interest. However, despite the considerable number of studies, a comprehensive overview of the main antioxidant molecules capable of counteracting OS-induced senescence is still lacking. Here, besides a brief description of the molecular mechanisms implicated in OS-mediated aging, we review and discuss the role of enzymes, mitochondria-targeting compounds, vitamins, carotenoids, organosulfur compounds, nitrogen non-protein molecules, minerals, flavonoids, and non-flavonoids as antioxidant compounds with an anti-aging potential, therefore offering insights into innovative lifespan-extending approaches.

Feasibility of Leukemia-Derived Exosome Enrichment and Co-isolated dsDNA Sequencing in Acute Myeloid Leukemia Patients: A Proof of Concept for New Leukemia Biomarkers Detection.

Exosomes are extracellular vesicles playing a pivotal role in the intercellular communication. They shuttle different cargoes, including nucleic acids from their cell of origin. For this reason, they have been studied as carriers of tumor markers in different liquid biopsy approaches, in particular for solid tumors. Few data are available concerning exosomes as markers of myeloid neoplasia. To better understand their real potential and the best approach to investigate leukemic exosomes, we present the results of a pilot feasibility study evaluating the application of next-generation sequencing analysis of dsDNA derived from exosomes isolated in 14 adult patients affected by acute myeloid leukemias. In particular, leukemia-derived exosome fractions have been analyzed. The concentration of dsDNA co-extracted with exosomes and the number and types of mutations detected were considered and compared with ones identified in the Bone Marrow (BM) and Peripheral Blood (PB) cells. Exosomal DNA concentration, both considering the cargo and the DNA surrounding the lipid membrane resulted in a linear correlation with leukemic burden. Moreover, exosomal DNA mutation status presented 86.5% of homology with BM and 75% with PB. The results of this pilot study confirmed the feasibility of a leukemia-derived exosome enrichment approach followed by exosomal dsDNA NGS analysis for AML biomarker detection. These data point to the use of liquid biopsy in myeloid neoplasia for the detection of active leukemic cells resident in the BM via a painless procedure.

Prevalence and demographic features of early-onset neurodegenerative dementia in Brescia County, Italy.

A few epidemiologic studies are available on the prevalence of early-onset Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD). The aim of this study was to establish in an Italian population, namely in Brescia County, the prevalence of early-onset neurodegenerative dementia, and how it is shared between AD and FTLD. A network among the participating centers has been established for 10 years. A standardized form was sent to be filled in for each patient. The census day was chosen as December 1, 2009. The prevalence of disease was calculated stratifying patients according to sex and diagnosis. On the census day, 175 patients in the whole population aged 45--65 years were enrolled into the study. The resulting overall prevalence of early-onset neurodegenerative dementia was found of 55.1 per 100,000 inhabitants (95%confidence interval, 47.0--63.4). A comparable prevalence between AD and FTLD was reported (25.5 and 29.6 per 100,000 inhabitants, respectively), and no differences in sex distribution were found both in AD and FTLD. The improvement of knowledge on early-onset neurodegenerative dementias allows us to reconsider its epidemiology and to rethink its impact on public polices. This would be crucial for defining the urgency of treatment approaches.

BDNF serum levels, but not BDNF Val66Met genotype, are correlated with personality traits in healthy subjects.

Consisting evidence in animal models has suggested that alterations in brain-derived neurotrophic factor (BDNF) brain expression and release are involved in the pathogenesis of mental illnesses, such as, mood, anxiety, and eating disorders. This hypothesis is supported by data emerging from biochemical studies on serum BDNF levels and genetic studies on the functional polymorphism Val66Met in the BDNF gene in patients and control subjects. Anxiety-related personality traits are associated with several mental disorders. However, they are also measurable in non-affected subjects and, so, may represent a useful "endophenotype" to study the biological correlation of the vulnerability factors in the general population. In this study, we analyzed putative correlations in subjects unaffected by mental disorders between personality traits, serum BDNF levels (N = 107), and the BDNF Val66Met genotype (N = 217). Furthermore, we tested the possible interactions between these variables. A significant correlation has been observed between high scores of harm avoidance (HA) measured by the temperament and character inventory (TCI), and low BDNF serum concentration (r = -0.253, P = 0.009). In addition, an association has been evidenced between low BDNF levels in serum and the BDNF Val/Val genotype (P = 0.021). By analyzing putative concomitant effects of different variables on HA scores in a regression model, we observed a significant correlation only with BDNF serum concentrations (P = 0.022). The study results suggest that a decrease in serum BDNF concentrations may represent a biochemical marker associated with anxiety personality traits also retrievable in the general population.

The influence of psychiatric screening in healthy populations selection: a new study and meta-analysis of functional 5-HTTLPR and rs25531 polymorphisms and anxiety-related personality traits.

BACKGROUND: A genetic liability for anxiety-related personality traits in healthy subjects has been associated with the functional serotonin transporter promoter polymorphism (5-HTTLPR), although the data are somewhat conflicting. Moreover, only one study has investigated the functional significance of the 5-HTTLPR/rs25531 haplotypes in relation to anxiety traits in healthy subjects. We tested whether the 5-HTTLPR polymorphism and the 5-HTTLPR/rs25531 haplotypes are linked to Harm Avoidance (HA) using an association study (STUDY I) and a meta-analytic approach (STUDY II). METHODS: STUDY I: A total of 287 unrelated Italian volunteers were screened for DSM-IV Axis I disorders and genotyped for the 5-HTTLPR and rs25531 (A/G) polymorphisms. Different functional haplotype combinations were also analyzed. STUDY II: A total of 44 studies were chosen for a meta-analysis of the putative association between 5-HTTLPR and anxiety-related personality traits. RESULTS: STUDY I: In the whole sample of 287 volunteers, we found that the SS genotype and S'S' haplotypes were associated with higher scores on HA. However, because the screening assessed by Mini-International Neuropsychiatric Interview (M.I.N.I.) showed the presence of 55 volunteers affected by depression or anxiety disorders, we analyzed the two groups ("disordered" and "healthy") separately. The data obtained did indeed confirm that in the "healthy" group, the significant effects of the SS genotype and S'S' haplotypes were lost, but they remained in the "disordered" group. STUDY II: The results of the 5-HTTLPR meta-analysis with anxiety-related traits in the whole sample confirmed the association of the SS genotype with higher anxiety-related traits scores in Caucasoids; however, when we analyzed only those studies that used structured psychiatric screening, no association was found. CONCLUSIONS: This study demonstrates the relevance to perform analyses on personality traits only in DSM-IV axis I disorder-free subjects. Furthermore, we did not find an association between functional serotonin transporter gene polymorphisms and anxiety traits in healthy subjects screened through a structured psychiatric interview.

Promising Intervention Approaches to Potentially Resolve Neuroinflammation And Steroid Hormones Alterations in Alzheimer's Disease and Its Neuropsychiatric Symptoms.

Neuroinflammation is a biological process by which the central nervous system responds to stimuli/injuries affecting its homeostasis. So far as this reactive response becomes exacerbated and uncontrolled, it can lead to neurodegeneration, compromising the cognitive and neuropsychiatric domains. Parallelly, modifications in the hypothalamic signaling of neuroprotective hormones linked also to the inflammatory responses of microglia and astrocytes can exacerbate these processes. To complicate the picture, modulations in the gut microbiota (GM) can induce changes in neuroinflammation, altering cognitive and neuropsychiatric functioning. We conducted a web-based search on PubMed. We described studies regarding the cross-talk among microglia and astrocytes in the neuroinflammation processes, along with the role played by the steroid hormones, and how this can reflect on cognitive decline/neurodegeneration, in particular on Alzheimer's Disease (AD) and its neuropsychiatric manifestations. We propose and support the huge literature showing the potentiality of complementary/alternative therapeutic approaches (nutraceuticals) targeting the sustained inflammatory response, the dysregulation of hypothalamic system and the GM composition. NF-κB and Keap1/Nrf2 are the main molecular targets on which a list of nutraceuticals can modulate the altered processes. Since there are some limitations, we propose a new intervention natural treatment in terms of Oxygen-ozone (O2-O3) therapy that could be potentially used for AD pathology. Through a meta-analytic approach, we found a significant modulation of O3 on inflammation-NF-κB/NLRP3 inflammasome/Toll-Like Receptor 4 (TLR4)/Interleukin IL-17α signalling, reducing mRNA (p<0.00001 Odd Ratio (OR)=-5.25 95% CI:-7.04/-3.46) and protein (p<0.00001 OR=-4.85 95%CI:-6.89/-2.81) levels, as well as on Keap1/Nrf2 pathway. Through anti-inflammatory, immune, and steroid hormones modulation and anti-microbial activities, O3 at mild therapeutic concentrations potentiated with nutraceuticals and GM regulators could determine combinatorial effects impacting on cognitive and neurodegenerative domains, neuroinflammation and neuroendocrine signalling, directly or indirectly through the mediation of GM.