Huntingtin CAG repeats in neuropathologically confirmed tauopathies: Novel insights.

Previous studies have suggested a relationship between the number of CAG triplet repeats in the HTT gene and neurodegenerative diseases not related to Huntington's disease (HD). This study seeks to investigate whether the number of CAG repeats of HTT is associated with the risk of developing certain tauopathies and its influence as a modulator of the clinical and neuropathological phenotype. Additionally, it aims to evaluate the potential of polyglutamine staining as a neuropathological screening. We genotyped the HTT gene CAG repeat number and APOE-ℰ isoforms in a cohort of patients with neuropathological diagnoses of tauopathies (n=588), including 34 corticobasal degeneration (CBD), 98 progressive supranuclear palsy (PSP) and 456 Alzheimer's disease (AD). Furthermore, we genotyped a control group of 1070 patients, of whom 44 were neuropathologic controls. We identified significant differences in the number of patients with pathological HTT expansions in the CBD group (2.7%) and PSP group (3.2%) compared to control subjects (0.2%). A significant increase in the size of the HTT CAG repeats was found in the AD compared to the control group, influenced by the presence of the Apoliprotein E (APOE)-ℰ4 isoform. Post-mortem assessments uncovered tauopathy pathology with positive polyglutamine aggregates, with a slight predominance in the neostriatum for PSP and CBD cases and somewhat greater limbic involvement in the AD case. Our results indicated a link between HTT CAG repeat expansion with other non-HD pathology, suggesting they could share common neurodegenerative pathways. These findings support that genetic or histological screening for HTT repeat expansions should be considered in tauopathies.

Macular vessel density in the superficial plexus is not associated to cerebrospinal fluid core biomarkers for Alzheimer's disease in individuals with mild cognitive impairment: The NORFACE cohort.

Background: Optical coherence tomography angiography (OCT-A) is a novel method in the dementia field that allows the detection of retinal vascular changes. The comparison of OCT-A measures with established Alzheimer's disease (AD)-related biomarkers is essential to validate the former as a marker of cerebrovascular impairment in the AD continuum. We aimed to investigate the association of macular vessel density (VD) in the superficial plexus quantified by OCT-A with the AT(N) classification based on cerebrospinal fluid (CSF) Aß1-42, p181-tau and t-tau measurements in individuals with mild cognitive impairment (MCI). Materials and methods: Clinical, demographic, ophthalmological, OCT-A and CSF core biomarkers for AD data from the Neuro-ophthalmology Research at Fundació ACE (NORFACE) project were analyzed. Differences in macular VD in four quadrants (superior, nasal, inferior, and temporal) among three AT(N) groups [Normal, Alzheimer and Suspected non-Alzheimer pathology (SNAP)] were assessed in a multivariate regression model, adjusted for age, APOE ε4 status, hypertension, diabetes mellitus, dyslipidemia, heart disease, chronic obstructive pulmonary disease and smoking habit, using the Normal AT(N) group as the reference category. Results: The study cohort comprised 144 MCI participants: 66 Normal AT(N), 45 Alzheimer AT(N) and 33 SNAP AT(N). Regression analysis showed no significant association of the AT(N) groups with any of the regional macular VD measures (all, p > 0.16). The interaction between sex and AT(N) groups had no effect on differentiating VD. Lastly, CSF Aß1-42, p181-tau and t-tau measures were not correlated to VD (all r < 0.13; p > 0.13). Discussion: Our study showed that macular VD measures were not associated with the AT(N) classification based on CSF biomarkers in patients with MCI, and did not differ between AD and other underlying causes of cognitive decline in our cohort.

Extracellular vesicles, the emerging mirrors of brain physiopathology.

Extracellular vesicles are secreted by a wide variety of cells, and their primary functions include intercellular communication, immune responses, human reproduction, and synaptic plasticity. Their molecular cargo reflects the physiological processes that their cells of origin are undergoing. Thus, many studies have suggested that extracellular vesicles could be a promising biomarker tool for many diseases, mainly due to their biological relevance and easy accessibility to a broad range of body fluids. Moreover, since their biological composition leads them to cross the blood-brain barrier bidirectionally, growing evidence points to extracellular vesicles as emerging mirrors of brain diseases processes. In this regard, this review explores the biogenesis and biological functions of extracellular vesicles, their role in different physiological and pathological processes, their potential in clinical practice, and the recent outstanding studies about the role of exosomes in major human brain diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), or brain tumors.

Plasma extracellular vesicles reveal early molecular differences in amyloid positive patients with early-onset mild cognitive impairment.

In the clinical course of Alzheimer's disease (AD) development, the dementia phase is commonly preceded by a prodromal AD phase, which is mainly characterized by reaching the highest levels of Aß and p-tau-mediated neuronal injury and a mild cognitive impairment (MCI) clinical status. Because of that, most AD cases are diagnosed when neuronal damage is already established and irreversible. Therefore, a differential diagnosis of MCI causes in these prodromal stages is one of the greatest challenges for clinicians. Blood biomarkers are emerging as desirable tools for pre-screening purposes, but the current results are still being analyzed and much more data is needed to be implemented in clinical practice. Because of that, plasma extracellular vesicles (pEVs) are gaining popularity as a new source of biomarkers for the early stages of AD development. To identify an exosome proteomics signature linked to prodromal AD, we performed a cross-sectional study in a cohort of early-onset MCI (EOMCI) patients in which 184 biomarkers were measured in pEVs, cerebrospinal fluid (CSF), and plasma samples using multiplex PEA technology of Olink© proteomics. The obtained results showed that proteins measured in pEVs from EOMCI patients with established amyloidosis correlated with CSF p-tau181 levels, brain ventricle volume changes, brain hyperintensities, and MMSE scores. In addition, the correlations of pEVs proteins with different parameters distinguished between EOMCI Aß( +) and Aß(-) patients, whereas the CSF or plasma proteome did not. In conclusion, our findings suggest that pEVs may be able to provide information regarding the initial amyloidotic changes of AD. Circulating exosomes may acquire a pathological protein signature of AD before raw plasma, becoming potential biomarkers for identifying subjects at the earliest stages of AD development.

The Synergic Effect of AT(N) Profiles and Depression on the Risk of Conversion to Dementia in Patients with Mild Cognitive Impairment.

Few studies have addressed the impact of the association between Alzheimer's disease (AD) biomarkers and NPSs in the conversion to dementia in patients with mild cognitive impairment (MCI), and no studies have been conducted on the interaction effect of these two risk factors. AT(N) profiles were created using AD-core biomarkers quantified in cerebrospinal fluid (CSF) (normal, brain amyloidosis, suspected non-Alzheimer pathology (SNAP) and prodromal AD). NPSs were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). A total of 500 individuals with MCI were followed-up yearly in a memory unit. Cox regression analysis was used to determine risk of conversion, considering additive and multiplicative interactions between AT(N) profile and NPSs on the conversion to dementia. A total of 224 participants (44.8%) converted to dementia during the 2-year follow-up study. Pathologic AT(N) groups (brain amyloidosis, prodromal AD and SNAP) and the presence of depression and apathy were associated with a higher risk of conversion to dementia. The additive combination of the AT(N) profile with depression exacerbates the risk of conversion to dementia. A synergic effect of prodromal AD profile with depressive symptoms is evidenced, identifying the most exposed individuals to conversion among MCI patients.

Symptomatic and Disease-Modifying Therapy Pipeline for Alzheimer's Disease: Towards a Personalized Polypharmacology Patient-Centered Approach.

Since 1906, when Dr. Alois Alzheimer first described in a patient "a peculiar severe disease process of the cerebral cortex", people suffering from this pathology have been waiting for a breakthrough therapy. Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder and the most common form of dementia in the elderly with a long presymptomatic phase. Worldwide, approximately 50 million people are living with dementia, with AD comprising 60-70% of cases. Pathologically, AD is characterized by the deposition of amyloid ß-peptide (Aß) in the neuropil (neuritic plaques) and blood vessels (amyloid angiopathy), and by the accumulation of hyperphosphorylated tau in neurons (neurofibrillary tangles) in the brain, with associated loss of synapses and neurons, together with glial activation, and neuroinflammation, resulting in cognitive deficits and eventually dementia. The current competitive landscape in AD consists of symptomatic treatments, of which there are currently six approved medications: three AChEIs (donepezil, rivastigmine, and galantamine), one NMDA-R antagonist (memantine), one combination therapy (memantine/donepezil), and GV-971 (sodium oligomannate, a mixture of oligosaccharides derived from algae) only approved in China. Improvements to the approved therapies, such as easier routes of administration and reduced dosing frequencies, along with the developments of new strategies and combined treatments are expected to occur within the next decade and will positively impact the way the disease is managed. Recently, Aducanumab, the first disease-modifying therapy (DMT) has been approved for AD, and several DMTs are in advanced stages of clinical development or regulatory review. Small molecules, mAbs, or multimodal strategies showing promise in animal studies have not confirmed that promise in the clinic (where small to moderate changes in clinical efficacy have been observed), and therefore, there is a significant unmet need for a better understanding of the AD pathogenesis and the exploration of alternative etiologies and therapeutic effective disease-modifying therapies strategies for AD. Therefore, a critical review of the disease-modifying therapy pipeline for Alzheimer's disease is needed.

Establishing In-House Cutoffs of CSF Alzheimer's Disease Biomarkers for the AT(N) Stratification of the Alzheimer Center Barcelona Cohort.

BACKGROUND: Clinical diagnosis of Alzheimer's disease (AD) increasingly incorporates CSF biomarkers. However, due to the intrinsic variability of the immunodetection techniques used to measure these biomarkers, establishing in-house cutoffs defining the positivity/negativity of CSF biomarkers is recommended. However, the cutoffs currently published are usually reported by using cross-sectional datasets, not providing evidence about its intrinsic prognostic value when applied to real-world memory clinic cases. METHODS: We quantified CSF Aß1-42, Aß1-40, t-Tau, and p181Tau with standard INNOTEST® ELISA and Lumipulse G® chemiluminescence enzyme immunoassay (CLEIA) performed on the automated Lumipulse G600II. Determination of cutoffs included patients clinically diagnosed with probable Alzheimer's disease (AD, n = 37) and subjective cognitive decline subjects (SCD, n = 45), cognitively stable for 3 years and with no evidence of brain amyloidosis in 18F-Florbetaben-labeled positron emission tomography (FBB-PET). To compare both methods, a subset of samples for Aß1-42 (n = 519), t-Tau (n = 399), p181Tau (n = 77), and Aß1-40 (n = 44) was analyzed. Kappa agreement of single biomarkers and Aß1-42/Aß1-40 was evaluated in an independent group of mild cognitive impairment (MCI) and dementia patients (n = 68). Next, established cutoffs were applied to a large real-world cohort of MCI subjects with follow-up data available (n = 647). RESULTS: Cutoff values of Aß1-42 and t-Tau were higher for CLEIA than for ELISA and similar for p181Tau. Spearman coefficients ranged between 0.81 for Aß1-40 and 0.96 for p181TAU. Passing-Bablok analysis showed a systematic and proportional difference for all biomarkers but only systematic for Aß1-40. Bland-Altman analysis showed an average difference between methods in favor of CLEIA. Kappa agreement for single biomarkers was good but lower for the Aß1-42/Aß1-40 ratio. Using the calculated cutoffs, we were able to stratify MCI subjects into four AT(N) categories. Kaplan-Meier analyses of AT(N) categories demonstrated gradual and differential dementia conversion rates (p = 9.815-27). Multivariate Cox proportional hazard models corroborated these findings, demonstrating that the proposed AT(N) classifier has prognostic value. AT(N) categories are only modestly influenced by other known factors associated with disease progression. CONCLUSIONS: We established CLEIA and ELISA internal cutoffs to discriminate AD patients from amyloid-negative SCD individuals. The results obtained by both methods are not interchangeable but show good agreement. CLEIA is a good and faster alternative to manual ELISA for providing AT(N) classification of our patients. AT(N) categories have an impact on disease progression. AT(N) classifiers increase the certainty of the MCI prognosis, which can be instrumental in managing real-world MCI subjects.

Characteristics of subjective cognitive decline associated with amyloid positivity.

INTRODUCTION: The evidence for characteristics of persons with subjective cognitive decline (SCD) associated with amyloid positivity is limited. METHODS: In 1640 persons with SCD from 20 Amyloid Biomarker Study cohort, we investigated the associations of SCD-specific characteristics (informant confirmation, domain-specific complaints, concerns, feelings of worse performance) demographics, setting, apolipoprotein E gene (APOE) ε4 carriership, and neuropsychiatric symptoms with amyloid positivity. RESULTS: Between cohorts, amyloid positivity in 70-year-olds varied from 10% to 76%. Only older age, clinical setting, and APOE ε4 carriership showed univariate associations with increased amyloid positivity. After adjusting for these, lower education was also associated with increased amyloid positivity. Only within a research setting, informant-confirmed complaints, memory complaints, attention/concentration complaints, and no depressive symptoms were associated with increased amyloid positivity. Feelings of worse performance were associated with less amyloid positivity at younger ages and more at older ages. DISCUSSION: Next to age, setting, and APOE ε4 carriership, SCD-specific characteristics may facilitate the identification of amyloid-positive individuals.

Effects of Nutrition on Cognitive Function in Adults with or without Cognitive Impairment: A Systematic Review of Randomized Controlled Clinical Trials.

New dietary approaches for the prevention of cognitive impairment are being investigated. However, evidence from dietary interventions is mainly from food and nutrient supplement interventions, with inconsistent results and high heterogeneity between trials. We conducted a comprehensive systematic search of randomized controlled trials (RCTs) published in MEDLINE-PubMed, from January 2018 to July 2021, investigating the impact of dietary counseling, as well as food-based and dietary supplement interventions on cognitive function in adults with or without cognitive impairment. Based on the search strategy, 197 eligible publications were used for data abstraction. Finally, 61 articles were included in the analysis. There was reasonable evidence that dietary patterns, as well as food and dietary supplements improved cognitive domains or measures of brain integrity. The Mediterranean diet showed promising results, whereas the role of the DASH diet was not clear. Healthy food consumption improved cognitive function, although the quality of these studies was relatively low. The role of dietary supplements was mixed, with strong evidence of the benefits of polyphenols and combinations of nutrients, but with low evidence for PUFAs, vitamin D, specific protein, amino acids, and other types of supplements. Further well-designed RCTs are needed to guide the development of dietary approaches for the prevention of cognitive impairment.

Investigation of male and female infertility in llamas and alpacas.

Llamas and alpacas are important production animals in South America, with increasing interest in other parts of the world. Poor reproductive efficiency combined with several unique anatomical and physiological reproductive features offer challenges in the diagnosis and treatment of infertility in camelids. This review presents an approach to the clinical investigation and common causes of infertility and subfertility in the male and female. The selection of males for breeding should be made based on complete evaluation to eliminate congenital and possibly hereditary disorders. Common disorders of the male reproductive system include testicular hypoplasia, testicular and epididymal cysts and testicular degeneration. Semen evaluation presents some challenges owing to the viscous nature of the ejaculate in these species. Females should be screened for congenital genital defects before breeding. Causes of subfertility in the female are dominated by ovarian and uterine disorders. A systematic clinical approach and the use of endometrial biopsy and advanced techniques, such as laparoscopy, allow early identification of these disorders. Further research is needed for continued understanding of the reproductive pathological processes in these species.

A highly efficient organogenesis protocol based on zeatin riboside for in vitro regeneration of eggplant.

BACKGROUND: Efficient organogenesis induction in eggplant (Solanum melongena L.) is required for multiple in vitro culture applications. In this work, we aimed at developing a universal protocol for efficient in vitro regeneration of eggplant mainly based on the use of zeatin riboside (ZR). We evaluated the effect of seven combinations of ZR with indoleacetic acid (IAA) for organogenic regeneration in five genetically diverse S. melongena and one S. insanum L. accessions using two photoperiod conditions. In addition, the effect of six different concentrations of indolebutyric acid (IBA) in order to promote rooting was assessed to facilitate subsequent acclimatization of plants. The ploidy level of regenerated plants was studied. RESULTS: In a first experiment with accessions MEL1 and MEL3, significant (p < 0.05) differences were observed for the four factors evaluated for organogenesis from cotyledon, hypocotyl and leaf explants, with the best results obtained (9 and 11 shoots for MEL1 and MEL3, respectively) using cotyledon tissue, 16 h light / 8 h dark photoperiod conditions, and medium E6 (2 mg/L of ZR and 0 mg/L of IAA). The best combination of conditions was tested in the other four accessions and confirmed its high regeneration efficiency per explant when using both cotyledon and hypocotyl tissues. The best rooting media was R2 (1 mg/L IBA). The analysis of ploidy level revealed that between 25 and 50% of the regenerated plantlets were tetraploid. CONCLUSIONS: An efficient protocol for organogenesis of both cultivated and wild accessions of eggplant, based on the use of ZR, is proposed. The universal protocol developed may be useful for fostering in vitro culture applications in eggplant requiring regeneration of plants and, in addition, allows developing tetraploid plants without the need of antimitotic chemicals.

Plasma Aß42/40 ratio alone or combined with FDG-PET can accurately predict amyloid-PET positivity: a cross-sectional analysis from the AB255 Study.

BACKGROUND: To facilitate population screening and clinical trials of disease-modifying therapies for Alzheimer's disease, supportive biomarker information is necessary. This study was aimed to investigate the association of plasma amyloid-beta (Aß) levels with the presence of pathological accumulation of Aß in the brain measured by amyloid-PET. Both plasma Aß42/40 ratio alone or combined with an FDG-PET-based biomarker of neurodegeneration were assessed as potential AD biomarkers. METHODS: We included 39 cognitively normal subjects and 20 patients with mild cognitive impairment from the AB255 Study who had undergone PiB-PET scans. Total Aß40 and Aß42 levels in plasma (TP42/40) were quantified using ABtest kits. Subjects were dichotomized as Aß-PET positive or negative, and the ability of TP42/40 to detect Aß-PET positivity was assessed by logistic regression and receiver operating characteristic analyses. Combination of plasma Aß biomarkers and FDG-PET was further assessed as an improvement for brain amyloidosis detection and diagnosis classification. RESULTS: Eighteen (30.5%) subjects were Aß-PET positive. TP42/40 ratio alone identified Aß-PET status with an area under the curve (AUC) of 0.881 (95% confidence interval [CI] = 0.779-0.982). Discriminating performance of TP42/40 to detect Aß-PET-positive subjects yielded sensitivity and specificity values at Youden's cutoff of 77.8% and 87.5%, respectively, with a positive predictive value of 0.732 and negative predictive value of 0.900. All these parameters improved after adjusting the model for significant covariates. Applying TP42/40 as the first screening tool in a sequential diagnostic work-up would reduce the number of Aß-PET scans by 64%. Combination of both FDG-PET scores and plasma Aß biomarkers was found to be the most accurate Aß-PET predictor, with an AUC of 0.965 (95% CI = 0.913-0.100). CONCLUSIONS: Plasma TP42/40 ratio showed a relevant and significant potential as a screening tool to identify brain Aß positivity in preclinical and prodromal stages of Alzheimer's disease.

67Ga as a biosensor of iron needs in different organs: Study performed on male and female rats subjected to iron deficiency and exercise.

The aim of the present study was to determine the iron needs in different organs and tissues using 67Ga as a biosensor in males and females rats subjected to iron deficiency (ID) and voluntary exercise (EX). 67Ga citrate was injected i.p. to female and male Wistar rats (n=5/sex/group). Groups: Control (sedentary conditions), Control+EX, ID and ID+EX. To determine the 67Ga uptake, samples from the following regions of interest (ROIs) were extracted 12h post-injection: blood, liver, gonads, bone marrow, heart, adrenal glands, skeletal muscle, stomach, kidney, eyeball, sciatic nerve, small intestine and peritoneum. The total 67Ga uptake was 412% higher in ID subjects than in control subjects, being 1011% higher in ID-males than ID-females. In ID-females, the ROIs with the greater 67Ga uptake were blood, kidney and bone marrow, while in ID-males they were sciatic nerve, eyeball and adrenals, which demonstrates that the biodistribution differed between sexes in sedentary conditions but when subjected to EX, the biodistribution was similar in each sex group although females had a greater 67Ga uptake. In ID+EX subjects, the ROIs that showed the highest uptake were sciatic nerve, eyeball and adrenal glands. Using 67Ga as a biosensor, it is possible to identify the needs of iron that each organ requires to perform their functions in normal physiological conditions. In addition, a higher or lower 67Ga uptake in a specific organ may indicate its malfunction or show damage.

Evaluation of Candidate Genes Related to Neuronal Apoptosis in Late-Onset Alzheimer's Disease.

The objective of this study was to identify genetic variation in genes encoding death receptors and signals that modulate their activity. After conducting a meta-analysis with five previous genome-wide association studies and aggregated data, the most significant signals, (TNF locus: rs2395488, rs2534672, and rs9267445; and FASLG locus: rs730278), were replicated in 1,046 cases and 372 controls. The rs2395488 and rs2534672 markers showed a modest protective effect (OR = 0.849, p = 0.49780;OR= 0.687, p = 0.11335), in contrast to rs730278 marker (OR = 1.146, p = 0.17212), which did not follow the previous effect direction; in any case it reached the significance level. Final meta-analysis, adding the replication sample, confirmed these observations. We concluded that FASLG marker is not etiologically linked to Alzheimer's disease. However, single nucleotide polymorphisms around TNF locus require further analyses in order to explain the association between Alzheimer's disease and human leukocyte antigen.

A colorectal cancer susceptibility new variant at 4q26 in the Spanish population identified by genome-wide association analysis.

BACKGROUND: Non-hereditary colorectal cancer (CRC) is a complex disorder resulting from the combination of genetic and non-genetic factors. Genome-wide association studies (GWAS) are useful for identifying such genetic susceptibility factors. However, the single loci so far associated with CRC only represent a fraction of the genetic risk for CRC development in the general population. Therefore, many other genetic risk variants alone and in combination must still remain to be discovered. The aim of this work was to search for genetic risk factors for CRC, by performing single-locus and two-locus GWAS in the Spanish population. RESULTS: A total of 801 controls and 500 CRC cases were included in the discovery GWAS dataset. 77 single nucleotide polymorphisms (SNP)s from single-locus and 243 SNPs from two-locus association analyses were selected for replication in 423 additional CRC cases and 1382 controls. In the meta-analysis, one SNP, rs3987 at 4q26, reached GWAS significant p-value (p = 4.02×10(-8)), and one SNP pair, rs1100508 CG and rs8111948 AA, showed a trend for two-locus association (p = 4.35×10(-11)). Additionally, our GWAS confirmed the previously reported association with CRC of five SNPs located at 3q36.2 (rs10936599), 8q24 (rs10505477), 8q24.21(rs6983267), 11q13.4 (rs3824999) and 14q22.2 (rs4444235). CONCLUSIONS: Our GWAS for CRC patients from Spain confirmed some previously reported associations for CRC and yielded a novel candidate risk SNP, located at 4q26. Epistasis analyses also yielded several novel candidate susceptibility pairs that need to be validated in independent analyses.

Early treatment of Kallmann syndrome may prevent eunuchoid appearance and behavior.

Kallmann syndrome (KS) is a genetic disorder which combines hypogonadotropic hypogonadism and anosmia. Hypogonadism is characterized by the absence or reduced levels of gonadotropin-releasing hormone and anosmia due to olfactory bulb aplasia. KS treatment usually begins just before puberty, but brain sexual maturation occurs long before puberty normally at perinatal age. As brain cells implicated in the development of the olfactory and reproductive system have a rostral and a caudal origin, and the rostral origin is affected by aplasia in KS and the caudal origin does not seem to be affected, the early treatment of KS, as proposed in this paper, is to attain brain sexual maturation at the most appropriate age possible to prevent the eunuchoid behavior and appearance observed in KS.

What is relationship between the medial preoptic area, the organum vasculosum of the lamina terminalis and Kallmann syndrome?

The medial preoptic area is a structure located in the hypothalamic anteroventral third ventricle region, and is closely related to the olfactory brain development and sexual differentiation of the brain. The medial preoptic area surrounds the organum vasculosum of the lamina terminalis, and both structures are the main areas where synthesis of gonadotropin-releasing hormone occurs in the brain. Neurons synthesizing gonadotropin-releasing hormone migrate from the medial nasal epithelium to the rostral brain and reach the organum vasculosum of the lamina terminalis and the medial preoptic area. Kallmann syndrome is a genetic disorder which combines hypogonadotropic hypogonadism and anosmia. Hypogonadism is characterized by the absence or reduced levels of gonadotropin-releasing hormone and anosmia due to olfactory bulb aplasia. This paper speculates on the connection between the development of the medial preoptic area, the organum vasculosum of the lamina terminalis and olfactory bulbs with Kallmann syndrome, since the anteroventral third ventricle region is crucial for the normal development of these structures and its connection with the olfactory nerves and sexual maturation.

Genome-wide association study of multiple sclerosis confirms a novel locus at 5p13.1.

Multiple Sclerosis (MS) is the most common progressive and disabling neurological condition affecting young adults in the world today. From a genetic point of view, MS is a complex disorder resulting from the combination of genetic and non-genetic factors. We aimed to identify previously unidentified loci conducting a new GWAS of Multiple Sclerosis (MS) in a sample of 296 MS cases and 801 controls from the Spanish population. Meta-analysis of our data in combination with previous GWAS was done. A total of 17 GWAS-significant SNPs, corresponding to three different loci were identified:HLA, IL2RA, and 5p13.1. All three have been previously reported as GWAS-significant. We confirmed our observation in 5p13.1 for rs9292777 using two additional independent Spanish samples to make a total of 4912 MS cases and 7498 controls (ORpooled = 0.84; 95%CI: 0.80-0.89; p = 1.36 × 10-9). This SNP differs from the one reported within this locus in a recent GWAS. Although it is unclear whether both signals are tapping the same genetic association, it seems clear that this locus plays an important role in the pathogenesis of MS.