Sex and Gender Differences in Neurodegenerative Diseases: Challenges for Therapeutic Opportunities.

The term "neurodegenerative diseases" (NDs) identifies a group of heterogeneous diseases characterized by progressive loss of selectively vulnerable populations of neurons, which progressively deteriorates over time, leading to neuronal dysfunction. Protein aggregation and neuronal loss have been considered the most characteristic hallmarks of NDs, but growing evidence confirms that significant dysregulation of innate immune pathways plays a crucial role as well. NDs vary from multiple sclerosis, in which the autoimmune inflammatory component is predominant, to more "classical" NDs, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. Of interest, many of the clinical differences reported in NDs seem to be closely linked to sex, which may be justified by the significant changes in immune mechanisms between affected females and males. In this review, we examined some of the most studied NDs by looking at their pathogenic and phenotypical features to highlight sex-related discrepancies, if any, with particular interest in the individuals' responses to treatment. We believe that pointing out these differences in clinical practice may help achieve more successful precision and personalized care.

Dysregulation of Gene Expressions in Multiple Sclerosis: TNFSF13B and Other Candidate Genes.

BACKGROUND: In previous investigations of combined miRNAs/mRNAs expressions in neurodegenerative diseases like Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS) we have targeted some interesting genes and molecular pathways that needed further confirmation. METHODS: By nanofluidic qPCR analysis, we aimed to verify the expression of genes that resulted differentially expressed in the previous analyses. Data from MS patients - either the pediatric and the adult occurrence of the disease (adMS and pedMS, respectively) - was compared to age-matched healthy groups. As neurological controls we recruited a cohort of ALS subjects, considering published searches of possible genetic similarities between the two diseases. RESULTS: The main results confirmed the involvement of most of the investigated genes in pedMS and adMS, like BACH2 and MICAL3. On the other hand, suggestive MS candidate genes like TNFSF13B showed an interesting trend possibly influenced by interfering factors, such as concomitant disease-modifying treatments; it is worth noting that TNFSF13B was one of the genes upregulated in ALS compared to age-matched adMS patients, together with the transcription factor TFDP1. CONCLUSIONS: Although with caution due to the small sample size, this study confirms the interest in transcriptomic analysis supported by integrated and educated bioinformatics evaluations, to shed further light in complex neurological diseases.

Combined microRNA and mRNA expression analysis in pediatric multiple sclerosis: an integrated approach to uncover novel pathogenic mechanisms of the disease.

Multiple sclerosis (MS) is a complex disease of the CNS that usually affects young adults, although 3-5% of cases are diagnosed in childhood and adolescence (hence called pediatric MS, PedMS). Genetic predisposition, among other factors, seems to contribute to the risk of the onset, in pediatric as in adult ages, but few studies have investigated the genetic 'environmentally naïve' load of PedMS. The main goal of this study was to identify circulating markers (miRNAs), target genes (mRNAs) and functional pathways associated with PedMS; we also verified the impact of miRNAs on clinical features, i.e. disability and cognitive performances. The investigation was performed in 19 PedMS and 20 pediatric controls (PCs) using a High-Throughput Next-generation Sequencing (HT-NGS) approach followed by an integrated bioinformatics/biostatistics analysis. Twelve miRNAs were significantly upregulated (let-7a-5p, let-7b-5p, miR-25-3p, miR-125a-5p, miR-942-5p, miR-221-3p, miR-652-3p, miR-182-5p, miR-185-5p, miR-181a-5p, miR-320a, miR-99b-5p) and 1 miRNA was downregulated (miR-148b-3p) in PedMS compared with PCs. The interactions between the significant miRNAs and their targets uncovered predicted genes (i.e. TNFSF13B, TLR2, BACH2, KLF4) related to immunological functions, as well as genes involved in autophagy-related processes (i.e. ATG16L1, SORT1, LAMP2) and ATPase activity (i.e. ABCA1, GPX3). No significant molecular profiles were associated with any PedMS demographic/clinical features. Both miRNAs and mRNA expressions predicted the phenotypes (PedMS-PC) with an accuracy of 92% and 91%, respectively. In our view, this original strategy of contemporary miRNA/mRNA analysis may help to shed light in the genetic background of the disease, suggesting further molecular investigations in novel pathogenic mechanisms.

Investigating the Role of MicroRNA and Transcription Factor Co-regulatory Networks in Multiple Sclerosis Pathogenesis.

MicroRNAs (miRNAs) and transcription factors (TFs) play key roles in complex multifactorial diseases like multiple sclerosis (MS). Starting from the miRNomic profile previously associated with a cohort of pediatric MS (PedMS) patients, we applied a combined molecular and computational approach in order to verify published data in patients with adult-onset MS (AOMS). Six out of the 13 selected miRNAs (miR-320a, miR-125a-5p, miR-652-3p, miR-185-5p, miR-942-5p, miR-25-3p) were significantly upregulated in PedMS and AOMS patients, suggesting that they may be considered circulating biomarkers distinctive of the disease independently from age. A computational and unbiased miRNA-based screening of target genes not necessarily associated to MS was then performed in order to provide an extensive view of the genetic mechanisms underlying the disease. A comprehensive MS-specific miRNA-TF co-regulatory network was hypothesized; among others, SP1, RELA, NF-κB, TP53, AR, MYC, HDAC1, and STAT3 regulated the transcription of 61 targets. Interestingly, NF-κB and STAT3 cooperatively regulate the expression of immune response genes and control the cross-talk between inflammatory and immune cells. Further functional analysis will be performed on the identified critical hubs. Above all, in our view, this approach supports the need of multidisciplinary strategies for shedding light into the pathogenesis of MS.

Meta-Analysis of Differential Connectivity in Gene Co-Expression Networks in Multiple Sclerosis.

Differential gene expression analyses to investigate multiple sclerosis (MS) molecular pathogenesis cannot detect genes harboring genetic and/or epigenetic modifications that change the gene functions without affecting their expression. Differential co-expression network approaches may capture changes in functional interactions resulting from these alterations. We re-analyzed 595 mRNA arrays from publicly available datasets by studying changes in gene co-expression networks in MS and in response to interferon (IFN)-ß treatment. Interestingly, MS networks show a reduced connectivity relative to the healthy condition, and the treatment activates the transcription of genes and increases their connectivity in MS patients. Importantly, the analysis of changes in gene connectivity in MS patients provides new evidence of association for genes already implicated in MS by single-nucleotide polymorphism studies and that do not show differential expression. This is the case of amiloride-sensitive cation channel 1 neuronal (ACCN1) that shows a reduced number of interacting partners in MS networks, and it is known for its role in synaptic transmission and central nervous system (CNS) development. Furthermore, our study confirms a deregulation of the vitamin D system: among the transcription factors that potentially regulate the deregulated genes, we find TCF3 and SP1 that are both involved in vitamin D3-induced p27Kip1 expression. Unveiling differential network properties allows us to gain systems-level insights into disease mechanisms and may suggest putative targets for the treatment.

Genome-wide association study in musician's dystonia: a risk variant at the arylsulfatase G locus?

Musician's dystonia (MD) affects 1% to 2% of professional musicians and frequently terminates performance careers. It is characterized by loss of voluntary motor control when playing the instrument. Little is known about genetic risk factors, although MD or writer's dystonia (WD) occurs in relatives of 20% of MD patients. We conducted a 2-stage genome-wide association study in whites. Genotypes at 557,620 single-nucleotide polymorphisms (SNPs) passed stringent quality control for 127 patients and 984 controls. Ten SNPs revealed P < 10(-5) and entered the replication phase including 116 MD patients and 125 healthy musicians. A genome-wide significant SNP (P < 5 × 10(-8) ) was also genotyped in 208 German or Dutch WD patients, 1,969 Caucasian, Spanish, and Japanese patients with other forms of focal or segmental dystonia as well as in 2,233 ethnically matched controls. Genome-wide significance with MD was observed for an intronic variant in the arylsulfatase G (ARSG) gene (rs11655081; P = 3.95 × 10(-9) ; odds ratio [OR], 4.33; 95% confidence interval [CI], 2.66-7.05). rs11655081 was also associated with WD (P = 2.78 × 10(-2) ) but not with any other focal or segmental dystonia. The allele frequency of rs11655081 varies substantially between different populations. The population stratification in our sample was modest (λ = 1.07), but the effect size may be overestimated. Using a small but homogenous patient sample, we provide data for a possible association of ARSG with MD. The variant may also contribute to the risk of WD, a form of dystonia that is often found in relatives of MD patients.

One year activity on subtraction MRI predicts subsequent 4 year activity and progression in multiple sclerosis.

OBJECTIVE: To investigate the predictive value of 1 year subtraction MRI (sMRI) on activity and progression over the next 4 years in early phase multiple sclerosis (MS). To compare sensitivity of sMRI and contrast enhanced MRI towards disease activity. METHODS: The study was performed on 127 MS patients with brain MRI within 5 years of symptom onset (y0), after 1 year (y1) and after 5 years (y5). Measures of clinical (Expanded Disability Status Scale, relapse rate) and conventional MRI outcomes (brain parenchyma fraction (BPF); T2 lesion volume (T2LV); contrast enhancing lesions (CEL)) were available at all time points. sMRI was obtained from y1-y0, y5-y1 and y5-y0 image pairs and the number of new, enlarged, resolved and regressed lesions was counted. RESULTS: One year lesion change measured by sMRI predicted sMRI lesion change (p<0.0001), BPF and T2LV (p<0.05) changes, as well as clinical relapse rate (p<0.02) in the subsequent 4 years. sMRI measures were retained in stepwise predictive models that included other candidate MRI predictors. Active lesions on sMRI over a 1, 4 or 5 year interval provided a more sensitive assessment of disease activity than number of CEL at y0, y1 and/or y5: 83%, 93% and 90% of patients without CEL showed sMRI activity during the y1-y0, y5-y1, and y5-y0 intervals. CONCLUSIONS: sMRI is a feasible and sensitive tool for detecting MS activity and may provide an alternative to contrast enhanced MRI in clinical practice, particularly in cases where CEL are not available or inconclusive. Furthermore, sMRI metrics combined with conventional MRI outcomes (CEL, T2LV, BPF) can increase the prediction of longer term MRI activity and progression.

Presenilin enhancer-2 gene: identification of a novel promoter mutation in a patient with early-onset familial Alzheimer's disease.

UNLABELLED: γ-Secretase proteins complex cleaves the amyloid precursor protein (APP) to generate amyloid-ß (Aß) peptides. Considerable evidence suggests that alterations in genes encoding these proteins exert their influence on the pathogenesis of familial Alzheimer's disease (FAD). Presenilin enhancer-2 gene (PEN-2) is a necessary component of the γ-Secretase complex. Recently, it has been shown that PEN-2 mutations could be involved in Alzheimer's disease (AD). We performed a mutational screening of all PEN-2 coding and promoter regions in a FAD cohort derived from Southern Italy. Four hundred and fifty-two subjects (FAD: 97; CONTROLS: 355) were recruited for this study. We identified for the first time in a key region necessary for the promoter activity a novel 3 bp deletion in a subject with early-FAD. Our genetic data demonstrate that the mutant allele may influence the transcriptional activity of the PEN-2 gene. Although the effective role of the PEN-2 promoter deletion in AD is not entirely clear, these findings might lead to more studies on its functional and genetic role.

An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients.

Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease's estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian MS multiplex family with five affected members. For this purpose, we combined linkage analysis and next-generation sequencing (NGS)-based whole exome and whole genome sequencing (WES and WGS, respectively). The genetic burden attributable to known common MS variants was also assessed by weighted genetic risk score (wGRS). We found a significantly higher burden of common variants in the affected family members compared to that observed among sporadic MS patients and healthy controls (HCs). We also identified 34 genes containing at least one low-frequency functional variant shared among all affected family members, showing a significant enrichment in genes involved in specific biological processes-particularly mRNA transport-or neurodegenerative diseases. Altogether, our findings point to a possible pathogenic role of different low-frequency functional MS variants belonging to shared pathways. We propose that these rare variants, together with other known common MS variants, may account for the high number of affected family members within this MS multiplex family.

Disease modeling in multiple sclerosis: assessment and quantification of sources of variability in brain parenchymal fraction measurements.

The measurement of brain atrophy from magnetic resonance imaging (MRI) has become an established method of estimating disease severity and progression in multiple sclerosis (MS). Most commonly reported in the form of brain parenchymal fraction (BPF), it is more sensitive to the degenerative component of the disease and shows progression more reliably than lesion burden. Typically, the reliability of BPF and other morphometric measurements is assessed by evaluating scan-rescan experiments. While these experiments provide good estimates of real-life error related to imperfect patient repositioning in the MRI scanner, measurement variance due to physiological and reversible pathological fluctuations in brain volume are not taken into account. In this work, we propose a new model for estimating variability in serial morphometry, particularly the BPF measurement. Specifically, we attempt to detect and explicitly model the remaining sources of error to more accurately describe the overall variability in BPF measurements. Our results show that sources of variability beyond subject repositioning error are important and cannot be ignored. We demonstrate that scan-rescan experiments only provide a lower bound on the true error in repeated measurements of patients' BPF. We have estimated the variance due to patient repositioning during scan-rescan (sigma(sr)(2) = 3.0e-06), variance assigned to physiological fluctuations (sigma(p)(2) = 5.74e-06) and the variance associated with lesion activity (sigma(les)(2) = 1.09e-05). These variance components can be used to determine the relative impact of their sources on sample size estimates for studies investigating change over time in MS patients. Our results demonstrate that sample size calculations based exclusively on scan-rescan variability (sigma(sr)) are likely to underestimate the number of patients required. If the physiological variability (sigma(p)) is incorporated in sample size calculations, the required sample size would increase by a factor of 5.69 based on standard t-test sample size calculation.

Neurobiological mechanisms underlying emotional processing in relapsing-remitting multiple sclerosis.

Affective disorders are frequent and disabling conditions in multiple sclerosis; however, the underlying neurobiological mechanisms are still poorly understood and investigated. Previous structural imaging studies have suggested that damage of frontal and temporal cortices plays an important role in the genesis of emotional disorders in multiple sclerosis, although psychosocial factors have been also implicated. However, this initial research may not have fully characterized the brain's functional dynamics of emotional processes in multiple sclerosis. Functional magnetic resonance imaging (fMRI) appears, therefore, to be a sensible tool to explore neurobiological mechanisms of emotions in multiple sclerosis since it also allows investigation of the functional connectivity or 'communication' between critical regions in affective behaviour [e.g. the prefrontal cortex (PFC) and amygdala]. In the present study, functional imaging was used to investigate the neural substrate of processing emotions in 12 multiple sclerosis patients relative to 12 healthy subjects matched for age and educational level. Only relapsing-remitting multiple sclerosis patients, who were cognitively unimpaired and who did not assume disease-modifying therapies, were included, given the potential confounding effect of these variables in the genesis of emotional symptoms. Brain responses were recorded in all participants while they executed an active task that consisted of processing emotional relative to neutral stimuli. Structural measures (i.e. total lesion load, grey matter, white matter and total brain volume) were also recorded to control for any effect of these variables. Despite similar performances during the task, and no differences in structural measures, multiple sclerosis patients displayed significantly greater responses within the ventrolateral PFC [t's > 5, P's < 0.02, Family Wise Error (FWE), small volume correction (svc)], compared to controls. Multiple sclerosis patients also showed a lack of functional connectivity between two prefrontal areas and the amygdala, a subcortical region critically involved in the generation of negative feelings (t's > 4, P's < 0.05, FWE, svc). It is likely that pathological changes related to the disease are reflected in an abnormal 'communication' between key emotional regions and that adaptive processes take place and become evident as enhanced responses of task-specific areas (i.e. the ventrolateral PFC). Local reorganizations in the brain can be viewed as compensatory mechanisms aimed to limit the clinical expression of emotional symptoms in multiple sclerosis. Overall our findings offer new insights into the neurobiological mechanisms of emotions in multiple sclerosis and provide evidence that they resemble those described for some psychiatric disorders.

OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes.

Mutations in OPA1, a dynamin-related GTPase involved in mitochondrial fusion, cristae organization and control of apoptosis, have been linked to non-syndromic optic neuropathy transmitted as an autosomal-dominant trait (DOA). We here report on eight patients from six independent families showing that mutations in the OPA1 gene can also be responsible for a syndromic form of DOA associated with sensorineural deafness, ataxia, axonal sensory-motor polyneuropathy, chronic progressive external ophthalmoplegia and mitochondrial myopathy with cytochrome c oxidase negative and Ragged Red Fibres. Most remarkably, we demonstrate that these patients all harboured multiple deletions of mitochondrial DNA (mtDNA) in their skeletal muscle, thus revealing an unrecognized role of the OPA1 protein in mtDNA stability. The five OPA1 mutations associated with these DOA 'plus' phenotypes were all mis-sense point mutations affecting highly conserved amino acid positions and the nuclear genes previously known to induce mtDNA multiple deletions such as POLG1, PEO1 (Twinkle) and SLC25A4 (ANT1) were ruled out. Our results show that certain OPA1 mutations exert a dominant negative effect responsible for multi-systemic disease, closely related to classical mitochondrial cytopathies, by a mechanism involving mtDNA instability.

Neurofunctional correlates of personality traits in relapsing-remitting multiple sclerosis: an fMRI study.

Extraversion and Neuroticism are two fundamental dimensions of human personality that influence cognitive functioning in healthy subjects. Little is known about personality changes that may occur in patients with multiple sclerosis (MS) nor about, in particular, their neurofunctional basis. The aim of this study is to determine the impact of personality characteristics on brain activity in patients with MS. Eighteen patients with clinically definite relapsing-remitting MS without any evidence of psychiatric or cognitive disorders and thirteen healthy controls matched for age, gender and education were investigated using functional magnetic resonance imaging (fMRI) during the execution of an "n-back" task. No differences were detected on the behavioral tests between the two groups, although the MS patients had lower total IQ and showed a trend towards higher Extraversion and Neuroticism scores than did the controls. fMRI analyses demonstrated that Extraversion scores were positively associated with brain activity in the fronto-parietal network including the superior parietal lobule and dorsolateral prefrontal cortex in both groups during the high load condition of the n-back task. Given the overlapping neural systems found in the two groups, we suggest that the neural activity associated with specific personality dimension is a neurophysiological characteristic preserved in patients with MS at an early stage in the course of their disease.

The MicroRNA Centrism in the Orchestration of Neuroinflammation in Neurodegenerative Diseases.

MicroRNAs (miRNAs) are small non-coding RNAs with a unique ability to regulate the transcriptomic profile by binding to complementary regulatory RNA sequences. The ability of miRNAs to enhance (proinflammatory miRNAs) or restrict (anti-inflammatory miRNAs) inflammatory signalling within the central nervous system is an area of ongoing research, particularly in the context of disorders that feature neuroinflammation, including neurodegenerative diseases (NDDs). Furthermore, the discovery of competing endogenous RNAs (ceRNAs) has led to an increase in the complexity of miRNA-mediated gene regulation, with a paradigm shift from a unidirectional to a bidirectional regulation, where miRNA acts as both a regulator and is regulated by ceRNAs. Increasing evidence has revealed that ceRNAs, including long non-coding RNAs, circular RNAs, and pseudogenes, can act as miRNA sponges to regulate neuroinflammation in NDDs within complex cross-talk regulatory machinery, which is referred to as ceRNA network (ceRNET). In this review, we discuss the role of miRNAs in neuroinflammatory regulation and the manner in which cellular and vesicular ceRNETs could influence neuroinflammatory dynamics in complex multifactorial diseases, such as NDDs.

Precision Medicine in Neurodegenerative Diseases: Some Promising Tips Coming from the microRNAs' World.

: Novel insights in the development of a precision medicine approach for treating the neurodegenerative diseases (NDDs) are provided by emerging advances in the field of pharmacoepigenomics. In this context, microRNAs (miRNAs) have been extensively studied because of their implication in several disorders related to the central nervous system, as well as for their potential role as biomarkers of diagnosis, prognosis, and response to treatment. Recent studies in the field of neurodegeneration reported evidence that drug response and efficacy can be modulated by miRNA-mediated mechanisms. In fact, miRNAs seem to regulate the expression of pharmacology target genes, while approved (conventional and non-conventional) therapies can restore altered miRNAs observed in NDDs. The knowledge of miRNA pharmacoepigenomics may offers new clues to develop more effective treatments by providing novel insights into interindividual variability in drug disposition and response. Recently, the therapeutic potential of miRNAs is gaining increasing attention, and miRNA-based drugs (for cancer) have been under observation in clinical trials. However, the effective use of miRNAs as therapeutic target still needs to be investigated. Here, we report a brief review of representative studies in which miRNAs related to therapeutic effects have been investigated in NDDs, providing exciting potential prospects of miRNAs in pharmacoepigenomics and translational medicine.

Integrated Analysis of microRNA and mRNA Expression Profiles: An Attempt to Disentangle the Complex Interaction Network in Attention Deficit Hyperactivity Disorder.

Attention Deficit Hyperactivity Disorder (ADHD) is a childhood-onset neurodevelopmental disorder, whose etiology and pathogenesis are still largely unknown. In order to uncover novel regulatory networks and molecular pathways possibly related to ADHD, we performed an integrated miRNA and mRNA expression profiling analysis in peripheral blood samples of children with ADHD and age-matched typically developing (TD) children. The expression levels of 13 miRNAs were evaluated with microfluidic qPCR, and differentially expressed (DE) mRNAs were detected on an Illumina HiSeq 2500 genome analyzer. The miRNA targetome was identified using an integrated approach of validated and predicted interaction data extracted from seven different bioinformatic tools. Gene Ontology (GO) and pathway enrichment analyses were carried out. Results showed that six miRNAs (miR-652-3p, miR-942-5p, let-7b-5p, miR-181a-5p, miR-320a, and miR-148b-3p) and 560 genes were significantly DE in children with ADHD compared to TD subjects. After correction for multiple testing, only three miRNAs (miR-652-3p, miR-148b-3p, and miR-942-5p) remained significant. Genes known to be associated with ADHD (e.g., B4GALT2, SLC6A9 TLE1, ANK3, TRIO, TAF1, and SYNE1) were confirmed to be significantly DE in our study. Integrated miRNA and mRNA expression data identified critical key hubs involved in ADHD. Finally, the GO and pathway enrichment analyses of all DE genes showed their deep involvement in immune functions, reinforcing the hypothesis that an immune imbalance might contribute to the ADHD etiology. Despite the relatively small sample size, in this study we were able to build a complex miRNA-target interaction network in children with ADHD that might help in deciphering the disease pathogenesis. Validation in larger samples should be performed in order to possibly suggest novel therapeutic strategies for treating this complex disease.

Association between miRNAs expression and cognitive performances of Pediatric Multiple Sclerosis patients: A pilot study.

INTRODUCTION: The Pediatric onset of Multiple Sclerosis (PedMS) occurs in up to 10% of all cases. Cognitive impairment is one of the frequent symptoms, exerting severe impact in patients' quality of life and school performances. The underlying pathogenic mechanisms are not fully understood, and molecular markers predictive of cognitive dysfunctions need to be identified. On these grounds, we searched for molecular signature/s (i.e., miRNAs and target genes) associated with cognitive impairment in a selected population of PedMS patients. Additionally, changes of their regional brain volumes associated with the miRNAs of interest were investigated. METHODS: Nineteen PedMS subjects received a full cognitive evaluation; total RNA from peripheral blood samples was processed by next-generation sequencing followed by a bioinformatics/biostatistics analysis. RESULTS: The expression of 11 miRNAs significantly correlated with the scores obtained at different cognitive tests; among the others, eight miRNAs correlated with the Trail Making Tests. The computational target prediction identified 337 genes targeted by the miRNAs of interest; a tangled network of molecular connections was hypothesized, where genes like BST1, NTNG2, SPTB, and STAB1, already associated with cognitive dysfunctions, were nodes of the net. Furthermore, the expression of some miRNAs significantly correlated with cerebral volumes, for example, four miRNAs with the cerebellum cortex. CONCLUSIONS: As far as we know, this is the first evaluation exploring miRNAs in the cognitive performances of PedMS. Although none of these results survived the multiple tests' corrections, we believe that they may represent a step forward the identification of biomarkers useful for monitoring and targeting the onset/progression of cognitive impairments in MS.

Impact of catechol-O-methyltransferase Val(108/158) Met genotype on hippocampal and prefrontal gray matter volume.

A variation in catechol-O-methyltransferase (COMT) gene (Val(108/158)Met) affects the physiological response of hippocampal-prefrontal circuits, predicts variation in human memory and is associated with increased risk for psychiatric disorders. Using optimized voxel-based morphometry we studied the effect of this functional polymorphism on the anatomy of the hippocampus, and the prefrontal cortex. Fifty-seven healthy participants were investigated (nine had Met/Met, 30 Val/Met, and 14 Val/Val). Voxel-based morphometry showed that individuals who are homozygous for the Val-COMT allele had greater gray matter volume of the prefrontal cortex bilaterally, whereas Met-COMT carriers were associated with increased tissue volume of the hippocampus bilaterally. This study provides evidence that the Val(108/158)Met polymorphism of the COMT gene might be responsible for individual variation in the human brain morphology.

Ventro-lateral prefrontal activity during working memory is modulated by MAO A genetic variation.

Several lines of evidence have highlighted the role of the serotonergic system in working memory (WM) processes. The X-linked Mono-Amine Oxidase A (MAO A) gene, coding for an enzyme especially involved in the serotonin (5-HT) catabolism, presents a well-characterized functional polymorphism consisting in a variable number of tandem repeats (VNTR) in the promoter region with high activity and low activity variants. The high activity allele carriers have been associated with higher enzyme expression, lower amine concentration and altered prefrontal cortex (PFC) function during motor inhibition, but a direct effect of MAO A genotype on WM-related brain activity has not been demonstrated. We have studied the relationship of this polymorphism to brain activity elicited by a spatial working memory task (n-back) using blood oxygenation level-dependent functional magnetic resonance imaging in 30 healthy male individuals matched for a series of demographic and genetic variables (COMT Val108/158Met). We show that the high activity allele was significantly (p-level<0,001) associated with increased activity of the right ventro-lateral PFC (VLPFC, BA 47) during the high load condition of the n-back task. Our data reveal pronounced genotype-related functional changes in specific prefrontal region (VLPFC) subserving spatial working memory. Moreover, given the well-known role of this area in inhibitory control, our finding also provides new evidence for the involvement of 5-HT in PFC-mediated WM function.