Analizan el papel de la proteincinasa C en la recuperación neuronal tras una lesión cerebral

Protein Kinase C: Targets to Regenerate Brain Injuries?

Abstract

Acute or chronic injury to the central nervous system (CNS), causes neuronal death and irreversible cognitive deficits or sensory-motor alteration. Despite the capacity of the adult CNS to generate new neurons from neural stem cells (NSC), neuronal replacement following an injury is a restricted process, which does not naturally result in functional regeneration. Therefore, potentiating endogenous neurogenesis is one of the strategies that are currently being under study to regenerate damaged brain tissue. The insignificant neurogenesis that occurs in CNS injuries is a consequence of the gliogenic/non-neurogenic environment that inflammatory signaling molecules create within the injured area. The modification of the extracellular signals to generate a neurogenic environment would facilitate neuronal replacement. However, in order to generate this environment, it is necessary to unearth which molecules promote or impair neurogenesis to introduce the first and/or eliminate the latter. Specific isozymes of the protein kinase C (PKC) family differentially contribute to generate a gliogenic or neurogenic environment in injuries by regulating the ADAM17 mediated release of growth factor receptor ligands. Recent reports describe several non-tumorigenic diterpenes isolated from plants of the Euphorbia genus, which specifically modulate the activity of PKC isozymes promoting neurogenesis. Diterpenes with 12-deoxyphorbol or lathyrane skeleton, increase NPC proliferation in neurogenic niches in the adult mouse brain in a PKCβ dependent manner exerting their effects on transit amplifying cells, whereas PKC inhibition in injuries promotes neurogenesis. Thus, compounds that balance PKC activity in injuries might be of use in the development of new drugs and therapeutic strategies to regenerate brain injuries.

Keywords:

ADAM17/TACE; brain injury; neurogenesis; neuroregeneration; protein kinase C

Un virus oncolítico mejora la supervivencia de un tumor cerebral pediátrico agresivo

The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models

Abstract

Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).

Introduction

Pediatric high-grade glioma (pHGG), including diffuse intrinsic pontine glioma (DIPG),

La depresión clínicamente relevante aumentaría el riesgo de demencia y enfermedad de Azlheimer en ancianos

Clinically relevant late-life depression as risk factor of dementia: a systematic review and meta-analysis of prospective cohort studies
O carry out a meta-analysis of population-based prospective cohort studies to investigate the risk of dementia and Alzheimer’s disease (AD) according to clinically relevant depression, assessed with Geriatric Mental State (GMS) criteria.

PATIENTS AND METHODS. 
A systematic literature search of the studies published in PubMed and Web of Science up to January 2018 was performed to identify all longitudinal studies on the association between clinically relevant depression (diagnosed with GMS criteria) and risk of dementia in the elderly. We calculated pooled relative risks to examine depression as a possible risk factor for dementia in community studies, as well as to compute population attributable fraction (PAF).

RESULTS. 
Six studies met inclusion criteria for the systematic review. All of them provided enough information to perform a meta-analysis. Participants with clinically relevant depression had a 54% higher risk of dementia (p = 0.026) with a PAF attributable to clinically relevant depression of 8.6%. The numbers for AD were 50% higher risk (p = 0.038) and a PAF of 10.8%. CONCLUSION. Clinically relevant depression is associated with an increased risk for dementia and AD in the community, with a potential impact higher than other known/recognized risk factors. Future studies should explore the mechanisms linking depression and dementia and AD as well as whether an effective treatment of clinically significant depression could prevent dementia and AD development.


































































Keywords
Alzheimer´s diseaseClinically relevant depressionDementiaMeta-analysisPublic health

Logran reconectar neuronas afectadas por degeneración frontotemporal en un modelo de ratón

Activity-Dependent Reconnection of Adult-Born Dentate Granule Cells in a Mouse Model of Frontotemporal Dementia

Abstract

Frontotemporal dementia (FTD) is characterized by neuronal loss in the frontal and temporal lobes of the brain. Here, we provide the first evidence of striking morphological alterations in dentate granule cells (DGCs) of FTD patients and in a mouse model of the disease, TauVLW mice. Taking advantage of the fact that the hippocampal dentate gyrus (DG) gives rise to newborn DGCs throughout the lifetime in rodents, we used RGB retroviruses to study the temporary course of these alterations in newborn DGCs of female TauVLW mice. In addition, retroviruses that encode either PSD95:GFP or Syn:GFP revealed striking alterations in the afferent and efferent connectivity of newborn TauVLW DGCs, and monosynaptic retrograde rabies virus tracing showed that these cells are disconnected from distal brain regions and local sources of excitatory innervation. However, the same cells exhibited a predominance of local inhibitory innervation. Accordingly, the expression of presynaptic and postsynaptic markers of inhibitory synapses was markedly increased in the DG of TauVLW mice and FTD patients. Moreover, an increased number of neuropeptide Y-positive interneurons in the DG correlated with a reduced number of activated egr-1+ DGCs in TauVLW mice. Finally, we tested the therapeutic potential of environmental enrichment and chemoactivation to reverse these alterations in mice. Both strategies reversed the morphological alterations of newborn DGCs and partially restored their connectivity in a mouse model of the disease. Moreover, our data point to remarkable morphological similarities between the DGCs of TauVLW mice and FTD patients.

Significance statement 

We show, for the first time to our knowledge, that the population of dentate granule cells is disconnected from other regions of the brain in the neurodegenerative disease frontotemporal dementia (FTD). These alterations were observed in FTD patients and in a mouse model of this disease. Moreover, we tested the therapeutic potential of two strategies, environmental enrichment and chemoactivation, to stimulate the activity of these neurons in mice. We found that some of the alterations were reversed by these therapeutic interventions.

• dentate granule cells (DGCs)
• DREADD
• environmental enrichment
• frontotemporal dementia (FTD)
• rabies virus
• RGB retrovirus

Vinculan niveles elevados de colesterol LDL con la enfermedad de Alzheimer de inicio temprano

Association of Early-Onset Alzheimer Disease With Elevated Low-Density Lipoprotein Cholesterol Levels and Rare Genetic Coding Variants of APOB

  
Abstract

Importance Early-onset Alzheimer disease (EOAD) is a rare form of Alzheimer disease (AD) with a large genetic basis that is only partially understood. In late-onset AD, elevated circulating cholesterol levels increase AD risk even after adjusting for the apolipoprotein E ε4 (APOE E4) allele, a major genetic factor for AD and elevated cholesterol levels; however, the role of circulating cholesterol levels in EOAD is unclear.

Objectives 

To investigate the association between circulating cholesterol levels and EOAD and to identify genetic variants underlying this possible association.

Design, Setting, and Participants 

 In this case series, plasma cholesterol levels were directly measured in 267 samples from the AD research centers (ADRCs) of Emory University and University of California, San Francisco, collected from January 21, 2009, through August 21, 2014. The association between cholesterol and EOAD was examined using multiple linear regression. To determine the underlying genetic variants, APOB, APP, PSEN1, and PSEN2 were sequenced in samples from 2125 EOAD cases and controls recruited from 29 ADRCs from January 1, 1984, through December 31, 2015. Data were analyzed from November 23, 2016, through April 10, 2018.

Exposures 

Clinical diagnosis, age at clinical diagnosis, plasma cholesterol measures (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B), and genetic variants in APOE, APP, PSEN1, PSEN2, and APOB.

Main Outcomes and Measures 

 The primary outcome was the association between EOAD and plasma cholesterol measures. The secondary outcome was the association between EOAD and the burden of genetic variants in APOB.

Results 

 Of the 2125 samples that underwent genetic sequencing, 1276 were from women (60.0%) and 654 (30.8%) were from patients with EOAD (mean [SD] ages, 55.6 [4.3] years for cases and 72.0 [9.6] years for controls). APOE E4 explained 10.1% of the variance of EOAD. After controlling for APOE E4, EOAD cases had higher levels of total cholesterol (mean difference [SE], 21.9 [5.2] mg/dL; P = 2.9 × 10−5), LDL-C (mean difference [SE], 22.0 [4.5] mg/dL; P = 1.8 × 10−6), and ApoB (mean difference [SE], 12.0 [2.4] mg/dL; P = 2.0 × 10−6) than controls in 267 frozen samples. Approximately 3% of EOAD cases carried known AD-causing mutations. Gene-based rare variant burden testing in 2066 samples showed that rare APOB coding variants were significantly more abundant in EOAD cases after adjusting for sex, APOE E4, genetic principal components, ADRC center, and batch (effect size, 0.20; P = 4.20 × 10−4).

Conclusions and Relevance 

 Elevated LDL-C levels were associated with higher probability of having EOAD, and EOAD cases were enriched for rare coding variants in APOB, which codes for the major protein of LDL-C. Collectively, these novel findings highlight the important role of LDL-C in EOAD pathogenesis and suggest a direct link of APOB variants to AD risk.

Nuevas evidencias sobre el efecto de la contaminación atmosférica en las capacidades cognitivas

Association between Early Life Exposure to Air Pollution and Working Memory and Attention

BACKGROUND: 

Although previous studies have reported negative associations between exposure to air pollution and cognition, studies of the effects of prenatal and postnatal exposures in early childhood have been limited.

OBJECTIVES:

We sought to assess the role exposure to fine particulate matter (PM2:5) during different prenatal and postnatal windows may play in children’s cognitive development at school age.

METHODS:

Within the Brain Development and Air Pollution Ultrafine Particles in School Children (BREATHE) Project, we estimated residential PM2:5 exposures by land use regression for the prenatal period and first seven postnatal years of 2,221 children from Barcelona, Spain. The participants (8:5±0:9 y old) completed computerized tests assessing working memory, attentiveness, and conflict network during four visits in 2012–2013. We used linear mixed effects and distributed lag models to assess the period of exposure to PM2:5 in association with cognitive development. RESULTS: Inverse associations were identified between PM2:5 exposure during the fifth and sixth postnatal years and working memory, with boys showing much higher vulnerability. Regarding attention functions, exposure to higher PM2:5 levels during the prenatal period and from the fourth postnatal year were associated with a reduction in conflict network performance, though we found no association with attentiveness. The overall estimated cumulative effect of a 10 lg m−3 increase in PM2:5 resulted in a reduction in the working memory d0 score of −19:50 [95% confidence interval (CI): −31:44, −7:57] points and an increase in the conflict attentional network of 11.31 (95% CI: 6.05, 16.57) milliseconds, indicating a poorer performance.

CONCLUSIONS:

Early life exposure to PM2:5 was associated with a reduction in fundamental cognitive abilities, including working memory and conflict attentional network.

https://doi.org/10.1289/EHP3169

Descifran aspectos del proceso de inflamación cerebral en la enfermedad de Alzheimer

Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease
Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer’s disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2–DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.

Keywords:

Alzheimer’s disease (AD) Galectin-3 TREM2 Microglia Inflammation Amyloid aggregation

Atención en urgencias de pacientes con cefalea sin criterios de alarma

Incidence of alarm criteria and attitude towards patients with headache attended in emergency departments

INTRODUCTION. 

Alarm criteria make it possible to identify persons who visit emergency services because of severe secondary headaches. AIMS. To determine the socio-demographic characteristics of the patients who visit emergency departments due to headache, the incidence of alarm criteria, treatment and the diagnosis after one year’s follow-up.

PATIENTS AND METHODS. 

We conducted a retrospective observational cross-sectional study of the persons attended in the emergency department of the Arnau de Vilanova Hospital between June 2014 and May 2015 due to headache.

RESULTS. 

A total of 303 persons were identified, of whom 165 were finally included in the study. There was a predominance of women (66.7%). The mean age was 41.2 ± 15.9 years. Only 16.4% were referred from primary care and 52 (31.5%) presented alarm criteria. A computerised tomography head scan was performed in half of these cases, and lumbar puncture was carried out in four of them (7.7%). A serious cause of headache was found in four cases (2.4%). After one year of follow-up, three patients who did not initially visit because of alarm criteria were diagnosed with severe diseases of the central nervous system, and 23 (13.9%) returned to the emergency department for the same reason.

CONCLUSIONS. 

Only one out of every two patients meets the alarm criteria. The proportion of severe secondary headache is really low. The multidisciplinary management of headache needs to be improved in our setting to prevent people visiting the emergency department due to primary headaches without any alarm criteria.

Una nueva molécula cartografía el sistema vascular cerebral

A ligand motif enables differential vascular targeting of endothelial junctions between brain and retina

Abstract

Endothelial heterogeneity has important implications in health and disease. Molecular markers selectively expressed in the vasculature of different organs and tissues are currently being explored in targeted therapies with promising results in preclinical and clinical studies. Noteworthy is the role that combinatorial approaches such as phage display have had in identifying such markers by using phage as nanoparticles and surrogates for billions of different peptides, screening noninvasively the vascular lumen for binding sites. Here, we show that a new peptide motif that emerged from such combinatorial screening of the vasculature binds selectively to blood vessels in the brain in vivo but not to vessels in other organs. Peptides containing a conserved motif in which amino acids Phenylalanine−Arginine−Tryptophan (FRW) predominate could be visualized by transmission electron microscopy bound to the junctions between endothelial cells in all areas of the brain, including the optic nerve, but not in other barrier-containing tissues, such as intestines and testis. Remarkably, peptides containing the motif do not bind to vessels in the retina, implying an important molecular difference between these two vascular barriers. Furthermore, the peptide allows for in vivo imaging, demonstrating that new tools for studying and imaging the brain are likely to emerge from this motif.

• blood−brain barrier
• blood−retina barrier
• brain endothelial cells
• peptide
• phage display

Trastorno bipolar como factor de riesgo de enfermedad de Parkinson

Bipolar disorder and risk of Parkinson disease. A nationwide longitudinal study

Abstract

Objective To evaluate the risk of Parkinson disease (PD) among patients with bipolar disorder (BD).

Methods Using the Taiwan National Health Insurance Research Database, we examined 56,340 patients with BD and 225,360 age- and sex-matched controls between 2001 and 2009 and followed them to the end of 2011. Individuals who developed PD during the follow-up period were identified.

Results Patients with BD had a higher incidence of PD (0.7% vs 0.1%, p < 0.001) during the follow-up period than the controls. A Cox regression analysis with adjustments for demographic data and medical comorbid conditions revealed that patients with BD were more likely to develop PD (hazard ratio [HR] 6.78, 95% confidence interval [CI] 5.74–8.02) than the control group. Sensitivity analyses after exclusion of the first year (HR 5.82, 95% CI 4.89–6.93) or first 3 years (HR 4.42; 95% CI 3.63–5.37) of observation showed consistent findings. Moreover, a high frequency of psychiatric admission for manic/mixed and depressive episodes was associated with an increased risk of developing PD.

Conclusion Patients with BD had a higher incidence of PD during the follow-up period than the control group. Manic/mixed and depressive episodes were associated with an elevated likelihood of developing PD. Further studies are necessary to investigate the underlying pathophysiology between BD and PD.

Imágenes en 3D para captar la deformación craneal de los bebés durante el parto

Three-dimensional magnetic resonance imaging of fetal head molding and brain shape changes during the second stage of labor

Abstract

To demonstrate and describe fetal head molding and brain shape changes during delivery, we used three-dimensional (3D) magnetic resonance imaging (MRI) and 3D finite element mesh reconstructions to compare the fetal head between prelabor and the second stage of labor. A total of 27 pregnant women were examined with 3D MRI sequences before going into labor using a 1 Tesla open field MRI. Seven of these patients subsequently had another set of 3D MRI sequences during the second stage of labor. Volumes of 2D images were transformed into finite element 3D reconstructions. Polygonal meshes for each part of the fetal body were used to study fetal head molding and brain shape changes. Varying degrees of fetal head molding were present in the infants of all seven patients studied during the second phase of labor compared with the images acquired before birth. The cranial deformation, however, was no longer observed after birth in five out of the seven newborns, whose post-natal cranial parameters were identical to those measured before delivery. The changing shape of the fetal brain following the molding process and constraints on the brain tissue were observed in all the fetuses. Of the three fetuses presenting the greatest molding of the skull bones and brain shape deformation, two were delivered by cesarean-section (one after a forceps failure and one for engagement default), while the fetus presenting with the greatest skull molding and brain shape deformation was born physiologically. This study demonstrates the value of 3D MRI study with 3D finite element mesh reconstruction during the second stage of labor to reveal how the fetal brain is impacted by the molding of the cranial bones. Fetal head molding was systematically observed when the fetal head was engaged between the superior pelvic strait and the middle brim. 

Un nuevo biomarcador en sangre permitiría diagnosticar la enfermedad de Alzheimer en estadios tempranos

Altered microRNAs related to synaptic function as potential plasma biomarkers for Alzheimer’s disease

Abstract

Several evidences suggest that failure of synaptic function occurs at preclinical stages of Alzheimer’s disease (AD) preceding neuronal loss and the classical AD pathological hallmarks. Nowadays, there is an urgent need to identify reliable biomarkers that could be obtained with non-invasive methods to improve AD diagnosis at early stages. Here, we have examined plasma levels of a group of miRNAs related to synaptic proteins in a cohort composed of cognitive healthy controls (HC), mild cognitive impairment (MCI) and AD subjects.

Methods

Plasma and brain levels of miRNAs were analysed in two different cohorts including 38 HC, 26 MCI, 56 AD dementia patients and 27 frontotemporal dementia (FTD) patients. D’Agostino and Pearson and Shapiro-Wilk tests were used to evaluate data normality. miRNA levels between groups were compared using a two-sided nonparametric Mann-Whitney test and sensitivity and specificity was determined by receiver operating characteristic curve analysis.

Results

Significant upregulation of miR-92a-3p, miR-181c-5p and miR-210-3p was found in the plasma of both MCI and AD subjects. MCI patients that progress to AD showed higher plasma levels of these miRNAs. By contrast, no changes in miR-92a-3p, miR-181c-5p or miR-210-3p levels were observed in plasma obtained from a cohort of FTD.

Conclusion

Our study shows that plasma miR-92a-3p, miR-181c-5p and miR-210-3p constitute a specific molecular signature potentially useful as a potential biomarker for AD. 

Descubren una nueva función de un enzima que podría intervenir en la prevención del síndrome de Prader-Willi

TET3 prevents terminal differentiation of adult NSCs by a non-catalytic action at Snrpn

Abstract

Ten-eleven-translocation (TET) proteins catalyze DNA hydroxylation, playing an important role in demethylation of DNA in mammals. Remarkably, although hydroxymethylation levels are high in the mouse brain, the potential role of TET proteins in adult neurogenesis is unknown. We show here that a non-catalytic action of TET3 is essentially required for the maintenance of the neural stem cell (NSC) pool in the adult subventricular zone (SVZ) niche by preventing premature differentiation of NSCs into non-neurogenic astrocytes. This occurs through direct binding of TET3 to the paternal transcribed allele of the imprinted gene Small nuclear ribonucleoprotein-associated polypeptide N (Snrpn), contributing to transcriptional repression of the gene. The study also identifies BMP2 as an effector of the astrocytic terminal differentiation mediated by SNRPN. Our work describes a novel mechanism of control of an imprinted gene in the regulation of adult neurogenesis through an unconventional role of TET3.

Uso de esteroides en neurooncología

Use of steroids in neuro-oncology

Abstract

Corticosteroids are widely used in routine clinical practice in neuro-oncology. However, despite their widespread use, there is no established consensus on their indications, dosages and dosage schedule. This article reviews the mechanism of action of corticosteroids, their indications for use, side effects and the appropriate management, dosage and duration of therapy, as well as the role of new treatments currently being use to treat cerebral oedema. The most widely used corticosteroid in neuro-oncology is dexamethasone, probably due to its low mineralocorticoid effect and its long half-life. Its effect on cerebral oedema is fundamental in the symptomatic control of patients with brain tumours. It is recommended to start treatment only in symptomatic patients, in doses of 4-8 mg/24 h, always seeking the minimum effective dosage. Side effects associated with corticosteroid use are common and have a negative impact on patients’ quality of life.

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Keywords Brain metastases Brain tumours Cerebral oedema Corticosteroids Dexamethasone Glioblastoma Neuro-oncology

La modulación de la vía de la vasopresina podría mejorar el funcionamiento social de personas con autismo

A phase 2 clinical trial of a vasopressin V1a receptor antagonist shows improved adaptive behaviors in men with autism spectrum disorder

Abstract

There are no approved pharmacological therapies to address the core symptoms of autism spectrum disorder (ASD), namely, persistent deficits in social communication and social interaction and the presence of restricted, repetitive patterns of behaviors, interests, or activities. The neuropeptide vasopressin has been implicated in the regulation of social behaviors, and its modulation has emerged as a therapeutic target for ASD. The phase 2 VANILLA clinical trial reported here evaluated balovaptan, an orally administered selective vasopressin V1a receptor antagonist, in 223 men with ASD and intelligence quotient ≥70. The drug was administered daily for 12 weeks and was compared with placebo. Participants were randomized to placebo (n = 75) or one of three balovaptan dose arms (1.5 mg, n = 32; 4 mg, n = 77; 10 mg, n = 39). Balovaptan treatment was not associated with a change from baseline compared with placebo at 12 weeks in the primary efficacy endpoint (Social Responsiveness Scale, 2nd Edition). However, dose-dependent and clinically meaningful improvements on the Vineland-II Adaptive Behavior Scales composite score were observed for participants treated with balovaptan 4 or 10 mg compared with placebo. This was driven principally by improvements in the Vineland-II socialization and communication scores. Balovaptan was well tolerated across all doses, and no drug-related safety concerns were identified. These results support further study of balovaptan as a potential treatment for the socialization and communication deficits in ASD.

Secuenciación del genoma para estudiar la enfermedad de Alzheimer en población argentina

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

Abstract

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

Introduction

Alzheimer’s disease (AD) is the most common form of dementia, and has an estimated genetic component of 60–80%1. Over the last decade, more than 20 loci containing common genetic variants (minor allele frequency (MAF) < 5%) have been associated with AD2. The advent of new genetic sequencing technologies has enabled the identification of several rare variants (MAF) < 1%) with moderate effects on AD susceptibility³. In 2017, the International Genomics of Alzheimer’s Project (IGAP) reported four rare coding variants significantly associated with AD4, all of them being involved in microglial-mediated innate immunity. Two of them are novel nonsynonymous variants: a protective one in PLCG2 (rs72824905) and a risk one in ABI3 (rs616338). The other two were previously reported in the susceptibility gene TREM2 (rs143332484 and rs75932628), and are responsible for p.R62H and p.R47H substitutions, respectively. The findings in TREM2 have been consistently replicated in Caucasian4,5,6 and African-American populations7. However, the association of TREM2 p.R47H with AD could not be found in East Asian population, because its frequency is extremely low8,9. This latter observation suggests ethnic variability fostering investigation of these variants in different ethnic groups. Given the increasing population diversity observed in countries all over the world, understanding population-shared and -specific risk factors of AD will translate into improved and specific prevention and/or treatment for people.

Latin America is a vast territory, with a wide diverse admixture of European, Native American, and African ancestral populations. The genetic architecture of sporadic AD has not been studied in this population beyond APOE-ε4. In this report, we provide the first evidence for an association between TREM2, PLCG2, and ABI3 rare variants and AD in the Argentinian population.

Cirugía en epilepsia refractaria debida a neurocisticercosis

Epilepsy surgery for refractory neurocysticercosis-related epilepsy

INTRODUCTION. 

Neurocysticercosis is one of the most frequent causes of epilepsy worldwide, with some cases going into refractoriness. For that reason, surgical treatment should be considered, particularly lesionectomy, with or without temporal lobectomy. CASE REPORTS. From our series of patients with drug-resistant epilepsy from 2008 to 2018, we selected all cases with one or more lesions suggestive of neurocysticercosis who underwent epilepsy surgery. Three patients fulfilled the inclusion criteria, with an average age of 39.33 year-old, two were female, epilepsy onset was at a mean age of 17.33 years. One case had multiple neurocysticercosis lesions and mesial temporal sclerosis, the other two cases had single neurocysticercosis lesions in the temporal region. In all cases, the epileptogenic zone was located in the temporal lobe. One patient underwent a temporal lobectomy, while the other two underwent lesionectomy. Pathology confirmed neurocysticercosis granuloma. All three cases remain seizure free. CONCLUSION. Evaluation of patients with neurocysticercosis-related refractory epilepsy for potential surgery is indicated, as this procedure can be quite successful.

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Keywords Epilepsy Epilepsy surgery Granuloma Lesionectomy Neurocysticercosis Refractory Classified in Epilepsias y síndromes epilépticos

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Nueva directriz de tratamiento de los tics y el síndrome de Tourette

Practice guideline recommendations summary: Treatment of tics in people with Tourette syndrome and chronic tic disorders
Abstract

Objective To make recommendations on the assessment and management of tics in people with Tourette syndrome and chronic tic disorders.

Methods A multidisciplinary panel consisting of 9 physicians, 2 psychologists, and 2 patient representatives developed practice recommendations, integrating findings from a systematic review and following an Institute of Medicine–compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence.

Results Forty-six recommendations were made regarding the assessment and management of tics in individuals with Tourette syndrome and chronic tic disorders. These include counseling recommendations on the natural history of tic disorders, psychoeducation for teachers and peers, assessment for comorbid disorders, and periodic reassessment of the need for ongoing therapy. Treatment options should be individualized, and the choice should be the result of a collaborative decision among patient, caregiver, and clinician, during which the benefits and harms of individual treatments as well as the presence of comorbid disorders are considered. Treatment options include watchful waiting, the Comprehensive Behavioral Intervention for Tics, and medication; recommendations are provided on how to offer and monitor these therapies. Recommendations on the assessment for and use of deep brain stimulation in adults with severe, treatment-refractory tics are provided as well as suggestions for future research.

Glossary

AAN=

American Academy of Neurology;

ADHD=

attention-deficit/hyperactivity disorder;

CBD=

cannabidiol;

CBIT=

Comprehensive Behavioral Intervention for Tics;

CBT=

cognitive behavioral therapy;

DBS=

deep brain stimulation;

DSM-5=

Diagnostic and Statistical Manual of Mental Disorders, 5th edition;

EVID=

evidence-based conclusions from the systematic review;

HRT=

habit reversal training;

INFER=

deductive inferences from other premises;

OCD=

obsessive-compulsive disorder;

PRIN=

generally accepted principles of care;

RELA=

strong evidence from related conditions;

THC=

δ-9-tetrahydrocannabinol;

TS=

Tourette syndrome;

VMAT2=

vesicular monoamine transporter type 2