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INTRODUCTION: Prolactinomas are the most frequent pituitary tumor subtype. Despite most of them respond to medical treatment, a proportion are resistant and become a challenge in clinical management. Wnt/β-Catenin pathway has been implicated in several cancers including pituitary tumors and other sellar region malignancies. Interestingly, Wnt/β-Catenin inhibition augments the cytotoxicity of the chemotherapeutic agent Temozolomide (TMZ) in different cancers. TMZ is now being implemented as rescue therapy for aggressive pituitary adenoma treatment. However, the molecular mechanisms associated with TMZ action in pituitary tumors remain unclear. OBJECTIVES: Our aims in the present study were to evaluate differential β-Catenin expression in human resistant prolactinomas and Wnt/β-Catenin signaling activation and involvement in Prolactin (PRL) secreting experimental models treated with TMZ. RESULTS: We first evaluated by immunohistochemistry β-Catenin localization in human resistant prolactinomas in which we demonstrated reduced membrane β-Catenin in prolactinoma cells compared to normal pituitaries, independently of the Ki-67 proliferation indexes. In turn, in vivo 15 mg/kg of orally administered TMZ markedly reduced PRL production and increased prolactinoma cell apoptosis in mice bearing xenografted prolactinomas. Intratumoral β-Catenin strongly correlated with Prl and Cyclin D1, and importantly, TMZ downregulated both β-Catenin and Cyclin D1, supporting their significance in prolactinoma growth and as candidates of therapeutic targets. When tested in vitro, TMZ directly reduced MMQ cell viability, increased apoptosis and produced G2/M cell cycle arrest. Remarkably, β-Catenin activation and VEGF secretion were inhibited by TMZ in vitro. CONCLUSIONS: We concluded that dopamine resistant prolactinomas undergo a β-Catenin relocalization in relation to normal pituitaries and that TMZ restrains experimental prolactinoma tumorigenicity by reducing PRL production and β-Catenin activation. Together, our findings contribute to the understanding of Wnt/β-Catenin implication in prolactinoma maintenance and TMZ therapy, opening the opportunity of new treatment strategies for aggressive and resistant pituitary tumors.

Primers sequences.

Figure S2. KANSL2 down regulation inhibits GBM derived tumor growth.

KANSL2 is an integral subunit of the nonspecific lethal (NSL) chromatin-modifying complex that contributes to epigenetic programs in embryonic stem cells. In this study, we report a role for KANSL2 in regulation of stemness in glioblastoma (GBM), which is characterized by heterogeneous tumor stem–like cells associated with therapy resistance and disease relapse. KANSL2 expression is upregulated in cancer cells, mainly at perivascular regions of tumors. RNAi-mediated silencing of KANSL2 in GBM cells impairs their tumorigenic capacity in mouse xenograft models. In clinical specimens, we found that expression levels of KANSL2 correlate with stemness markers in GBM stem–like cell populations. Mechanistic investigations showed that KANSL2 regulates cell self-renewal, which correlates with effects on expression of the stemness transcription factor POU5F1. RNAi-mediated silencing of POU5F1 reduced KANSL2 levels, linking these two genes to stemness control in GBM cells. Together, our findings indicate that KANSL2 acts to regulate the stem cell population in GBM, defining it as a candidate GBM biomarker for clinical use. Cancer Res; 76(18); 5383–94. ©2016 AACR.

Additional supporting experimental information.

Background Children ≤36 months with diffuse intrinsic pontine glioma (DIPG) have increased long-term survival (LTS, overall survival (OS) ≥24 months). Understanding distinguishing characteristics in this population is critical to improving outcomes. Methods Patients ≤36 months at diagnosis enrolled on the International DIPG Registry (IDIPGR) with central imaging confirmation were included. Presentation, clinical course, imaging, pathology and molecular findings were analyzed. Results Among 1183 patients in IDIPGR, 40 were eligible (median age: 29 months). Median OS was 15 months. Twelve patients (30%) were LTS, 3 (7.5%) very long-term survivors ≥5 years. Among 8 untreated patients, median OS was 2 months. Patients enrolled in the registry but excluded from our study by central radiology review or tissue diagnosis had median OS of 7 months. All but 1 LTS received radiation. Among 32 treated patients, 1-, 2-, 3-, and 5-year OS rates were 68.8%, 31.2%, 15.6% and 12.5%, respectively. LTS had longer duration of presenting symptoms (P = .018). No imaging features were predictive of outcome. Tissue and genomic data were available in 18 (45%) and 10 patients, respectively. Among 9 with known H3K27M status, 6 had a mutation. Conclusions Children ≤36 months demonstrated significantly more LTS, with an improved median OS of 15 months; 92% of LTS received radiation. Median OS in untreated children was 2 months, compared to 17 months for treated children. LTS had longer duration of symptoms. Excluded patients demonstrated a lower OS, contradicting the hypothesis that children ≤36 months with DIPG show improved outcomes due to misdiagnosis.

Alzheimer’s disease is a neurodegenerative disorder characterized clinically by cognitive decline and pathologically by amyloid deposition and neurofibrillary changes. These neuropathological hallmarks are accompanied by reactive events including microglial activation and astrogliosis. The inflammatory response in Alzheimer’s disease brains is distinguished by a pro-inflammatory signature involving amyloid peptides1, inflammasome signaling2 and disrupted blood brain barrier3. Inflammatory changes are observed also in the cerebrospinal fluid in Alzheimer’s disease4,5. It remains unknown, however, whether the choroid plexus which produces cerebrospinal fluid and guards the brain from peripheral inflammatory insults6,7, contributes to the inflammation and pathogenesis of Alzheimer’s disease. Here we show that the choroid plexus in Alzheimer’s disease exhibits a pro-inflammatory signature with aberrant protein accumulations, which contribute to the age-dependent inflammatory changes observed in the cerebrospinal fluid. Magnetic resonance imaging reveals that the choroid plexus in patients with Alzheimer’s disease displays pathological signal and increased volume, which inversely correlates with cognitive decline. Our findings suggest that the choroid plexus, being unable to efficiently resolve inflammatory insults over the lifetime, eventually ignites and drives the aberrant inflammatory response observed in Alzheimer’s disease. These findings advance our understanding of the pathogenesis and open new vistas in the diagnostics and therapeutics of Alzheimer’s disease.

Background Diffuse intrinsic pontine glioma (DIPG) remains a clinico-radiologic diagnosis without routine tissue acquisition. Reliable imaging distinction between DIPG and other pontine tumors with potentially more favorable prognoses and treatment considerations is essential. Methods Cases submitted to the International DIPG registry (IDIPGR) with histopathologic and/or radiologic data were analyzed. Central imaging review was performed on diagnostic brain MRIs (if available) by two neuro-radiologists. Imaging features suggestive of alternative diagnoses included nonpontine origin, Results Among 286 patients with pathology from biopsy and/or autopsy, 23 (8%) had histologic diagnoses inconsistent with DIPG, most commonly nondiffuse low-grade gliomas and embryonal tumors. Among 569 patients with centrally-reviewed diagnostic MRIs, 40 (7%) were classified as non-DIPG, alternative diagnosis suspected. The combined analysis included 151 patients with both histopathology and centrally-reviewed MRI. Of 77 patients with imaging classified as characteristic of DIPG, 76 (99%) had histopathologic diagnoses consistent with DIPG (infiltrating grade II-IV gliomas). Of 57 patients classified as likely DIPG with some unusual imaging features, 55 (96%) had histopathologic diagnoses consistent with DIPG. Of 17 patients with imaging features suggestive of an alternative diagnosis, eight (47%) had histopathologic diagnoses inconsistent with DIPG (remaining patients were excluded due to nonpontine tumor origin). Association between central neuro-imaging review impression and histopathology was significant (p < 0.001), and central neuro-imaging impression was prognostic of overall survival. Conclusions The accuracy and important role of central neuro-imaging review in confirming the diagnosis of DIPG is demonstrated.

Objective Cerebral amyloid angiopathy-related inflammation (CAA-RI) is a rare and potentially treatable encephalopathy that usually affects people older than 50 years old and has an acute or subacute clinical presentation characterized by rapidly evolving cognitive decline, focal deficits and seizures. In a small subset of patients the disease can adopt a pseudotumoral form in the neuroimages that represents a very difficult diagnostic challenge.Methods Here in we report a patient with a tumour-like presentation of histopathologically confirmed CAA-RI.Results We also conducted a search and reviewed the clinical and radiological features of 41 cases of pseudotumoral CAA-RI previously reported in the literature in order to identify those characteristics that should raise diagnostic suspicions of the disease, there by avoiding unnecessary surgical treatments.Conclusion The therapy of CAA-RI with steroids is usually effective and clinical and radiological remission can be achieved in the first month in approximately 70% of cases.

Objective: This study aimed to investigate the role and prognosis of Alzheimer disease biomarkers in patients with mild cognitive impairment (MCI) at a memory clinic in Latin America. Methods: We studied 89 patients with MCI, 43 with Alzheimer-type dementia, and 18 healthy controls (matched for age, sex, and educational level) at our memory clinic (Instituto FLENI) in Buenos Aires, Argentina. Patients and controls underwent an extensive demographic, neurological, and neuropsychological assessment. All subjects underwent a brain MRI scan; FDG-PET scan; amyloid PET scan; apolipoprotein E genotyping; and cerebrospinal fluid concentrations of Aβ1-42, tau, and phosphorylated tau. Patients were categorised as positive or negative for the presence of amyloid pathology and neurodegeneration. Results: Amyloid pathology was observed in cerebrospinal fluid results in 18% of controls, 64% of patients with MCI, and 92% of patients with Alzheimer-type dementia. Suspected non–Alzheimer disease pathophysiology was found in 11% of controls, 6% of patients with MCI, and 8% of patients with Alzheimer-type dementia. At 30 months of follow-up, 45% of amyloid-positive patients with MCI and 20% of amyloid-negative patients with MCI showed progression to dementia. Conclusions: This study demonstrates biomarker-based MCI prognosis and supports its role in clinical decision-making in daily practice. Objetivo: este estudio tuvo como objetivo investigar el papel y el pronóstico de los biomarcadores de la enfermedad de Alzheimer en pacientes con deterioro cognitivo leve (MCI) en una clínica de memoria en América Latina. Métodos: Estudiamos 89 pacientes con LM, 43 con demencia de tipo Alzheimer y 18 controles sanos (emparejados por edad, sexo y nivel educativo) en nuestra clínica de memoria (Instituto FLENI) en Buenos Aires, Argentina. Los pacientes y los controles se sometieron a una extensa evaluación demográfica, neurológica y neuropsicológica. Todos los sujetos se sometieron a una resonancia magnética cerebral; FDG-PET scan; tomografía PET amiloide; apolipoproteína E genotipado; y concentraciones de líquido cefalorraquídeo de Aβ1-42, tau y tau fosforilada. Los pacientes fueron categorizados como positivos o negativos por la presencia de patología amiloide y neurodegeneración. Resultados: se observó patología de amiloide en los resultados del líquido cefalorraquídeo en el 18% de los controles, el 64% de los pacientes con LM y el 92% de los pacientes con demencia de tipo Alzheimer. La sospecha de fisiopatología no relacionada con la enfermedad de Alzheimer se encontró en el 11% de los controles, el 6% de los pacientes con MCI y el 8% de los pacientes con demencia de tipo Alzheimer. A los 30 meses de seguimiento, el 45% de los pacientes con amiloide positivo con MCI y el 20% de los pacientes con amiloide negativo con MCI mostraron progresión a demencia. Conclusiones: este estudio demuestra el pronóstico de MCI basado en biomarcadores y apoya su papel en la toma de decisiones clínicas en la práctica diaria.

Epithelial to mesenchymal transition (EMT) is a critical cellular process that has been well characterized during embryonic development and cancer metastasis and it also is implicated in several physiological and pathological events including embryonic stem cell differentiation. During early stages of differentiation, human embryonic stem cells pass through EMT where deeper morphological, molecular and biochemical changes occur. Though initially considered as a decision between two states, EMT process is now regarded as a fluid transition where cells exist on a spectrum of intermediate states. In this work, using a CRISPR interference system in human embryonic stem cells, we describe a molecular characterization of the effects of downregulation of E-cadherin, one of the main initiation events of EMT, as a unique start signal. Our results suggest that the decrease and delocalization of E-cadherin causes an incomplete EMT where cells retain their undifferentiated state while expressing several characteristics of a mesenchymal-like phenotype. Namely, we found that E-cadherin downregulation induces SNAI1 and SNAI2 upregulation, promotes MALAT1 and LINC-ROR downregulation, modulates the expression of tight junction occludin 1 and gap junction connexin 43, increases human embryonic stem cells migratory capacity and delocalize β-catenin. Altogether, we believe our results provide a useful tool to model the molecular events of an unstable intermediate state and further identify multiple layers of molecular changes that occur during partial EMT.

Resumen Objetivo Analizar características por resonancia magnética (RM) de gliomas IDH-mutados (grado II y III) en base a parámetros cualitativos, a fin de valorar el rendimiento del signo del mismatch T2-FLAIR y otras características morfológicas de los tumores, en predecir el estado del 1p/19q y su reproducibilidad interobservador. Métodos Estudio retrospectivo, descriptivo y analítico sobre una cohorte de 53 gliomas IDH-mutados (grado II y III) y molecularmente definidos respecto al 1p/19q, seleccionados a partir de la base de datos de la institución, durante el periodo 2014–2019. Dos neuroradiólogos evaluaron características imagenológicas de forma independiente y enmascarada al diagnóstico: mismatch T2-FLAIR, localización tumoral, bordes, señal, infiltración cortical e inhomogeneidad en T2*. Los casos discordantes fueron evaluados por un tercer neuroradiólogo de mayor experiencia. Resultados Treinta de 53 (56,6%) gliomas fueron no codelecionados, y 23/53 (43,4%) codelecionados. El signo del mismatch T2-FLAIR fue positivo en 16/53 (30,18%) pacientes, 15/16 (93,75%) no codelecionados y 1/16 (6,25%) codelecionado (Exacto de Fisher p= Discusión La reciente actualización en la clasificación de los gliomas los clasifica acorde a su perfil molecular. En los últimos años, varios investigadores han estudiado características morfológicas por RM de los tumores con la intención de predecir las características moleculares de los mismos. Conclusión En nuestra población, el signo del mismatch T2-FLAIR es el único biomarcador radiológico que muestra asociación estadísticamente significativa en predecir la ausencia de codeleción en los gliomas IDH-mutados (grado II y III), con una alta especificidad y un alto valor predictivo positivo.

Resumen Introduccion y objetivo Una conmocion cerebral es un tipo de lesion cerebral traumatica que afecta la funcion normal del cerebro. Ocurre cuando el cerebro se mueve dentro del craneo como resultado de un golpe en la cabeza o el cuerpo. El objetivo de este articulo es presentar un protocolo para el reconocimiento y el manejo de la conmocion cerebral en los deportes. Metodos Se realizo una busqueda sistematica en las bases de datos Medline, PsycINFO y SciELO y en las fuentes electronicas de las diferentes asociaciones deportivas desde 2010 hasta enero de 2018. La busqueda se centro en guias de practica clinica, revisiones sistematicas, metaanalisis y ensayos clinicos aleatorizados controlados. Resultados En base a preguntas clinicas elaboradas por el grupo de expertos, se presentan recomendaciones para el manejo de la conmocion cerebral asociada al deporte. Las etapas clave en el proceso de toma de decisiones son: 1) Educacion sobre conmocion cerebral, identificacion de lesiones cerebrales y riesgos asociados; 2) Retiro del juego por sospecha de conmocion cerebral; y 3) Regreso al juego despues de la evaluacion por un profesional entrenado. Conclusiones El presente protocolo desarrollado por el grupo de estudio de las conmociones cerebrales asociadas al deporte en Argentina (Arg-SCoS) se diseno con el objetivo de desarrollar un marco de referencia para la evaluacion y manejo de la conmocion cerebral en el deporte. Se realizara una actualizacion de la revision bibliografica a partir de la fecha de publicacion, cada 3 anos.

Mesenchymal Stem Cells derived from induced Pluripotent Stem cells (iPSC-MSC) have become a promising alternative to classical Mesenchymal Stem Cells in regenerative medicine. Their properties -as immunomodulatory and regenerative capacities-are in part due to the secretion of Extracellular Vesicles (EVs). Small EVs (sEVs) with sizes that range from 50 to 120 nm contain proteins, lipids, and nucleic acids that exert a role in cellular communication. Their content will depend on the cell of origin and its physiological state, thus the message they convey might change in response to changes in cellular conditions. In particular, the DNA damage response (DDR) has been reported to modulate sEVs secretion. In this work, we analyze how UV-C radiation upon iPSC-MSC alter sEVs secretion, cargo and bystander effect. Here, we confirm that UV-C radiation causes DDR in a dose dependent manner. In addition, we found that UV-C induced stress did not modulate the expression of genes that participate in sEVs biogenesis pathway. Consequently, we found that the amount of sEVs secreted by radiated and non-irradiated cells remained stable. However, sEVs from radiated cells were unable to promote cell migration in their target cells. Moreover, a label-free proteomic analysis revealed that UV-C induced DDR produces sEVs with an altered cargo, rich in migration-inhibiting proteins, and resulting in a less stromal-oriented repertoire.

Sequence variants in exon 2 of the Dynactin-1 gene (DCTN1) have been reported as causative of Perry (disease) Syndrome (PeD, MIM 168605), a rare neurodegenerative disorder characterized by parkinsonism, psychiatric symptoms, weight loss and hypoventilation [1]. Here, we report the third family with the p.G67D variant in DCTN1. An Argentine family from the northeastern province of Misiones was evaluated at multiple centers. Three individuals were available for clinical, neuropsychological and genetic testing including the proband (Fig. 1, individual III.2), a symptomatic sister (III.3), and an asymptomatic brother (III.4). All family members and/or caregivers gave their informed consent to participate. This investigation was approved by the Institutional Ethics Committee., Fil: Silva, Emanuel. UCAMI Universidad Católica de las Misiones Posadas. Predigma Centro de Medicina Preventiva; Argentina, Fil: Itzcovich, Tatiana. Fleni. Departamento de Neuropatología y Biología Molecular. Laboratorio de Enfermedades Neurodegenerativas; Argentina, Fil: Niikado, Matías. Departamento de Neuropatología y Biología Molecular. Laboratorio de Enfermedades Neurodegenerativas; Argentina, Fil: Caride, Alejandro. Hospital Alemán. Servicio de Neurología; Argentina, Fil: Fernández, Elmer. Universidad Católica de Córdoba. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas; Argentina, Fil: Fernández, Elmer. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina, Fil: Vázquez, Juan Carlos. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina, Fil: Vázquez, Juan Carlos. Universidad Tecnológica Nacional. Facultad Regional Córdoba. Grupo de Investigación en Aprendizaje Automático, Lenguajes y Autómatas; Argentina, Fil: Romorini, Leonardo. Fleni. Laboratorio de Investigación Aplicada a las Neurociencias (LIAN); Argentina, Fil: Romorini, Leonardo. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Argentina, Fil: Marazita, Mariela. Fleni. Laboratorio de Investigación Aplicada a las Neurociencias (LIAN); Argentina, Fil: Marazita, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Argentina, Fil: Sevlever, Gustavo. Fleni. Departamento de Neuropatología y Biología Molecular. Laboratorio de Enfermedades Neurodegenerativas; Argentina, Fil: Martinetto, Horacio. Fleni. Departamento de Neuropatología y Biología Molecular. Laboratorio de Enfermedades Neurodegenerativas; Argentina, Fil: Surace, Ezequiel I. Fleni. Departamento de Neuropatología y Biología Molecular. Laboratorio de Enfermedades Neurodegenerativas; Argentina, Fil: Surace, Ezequiel I. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Argentina

Induced pluripotent stem cells (iPSC) have a great potential, but their clinical application depends on finding strategies to abolish their tumorigenic potential. The use of Oct4, Sox2, Klf4, c-Myc and Nanog to generate iPSC demonstrated the already known importance of these genes to maintain stemness. Therefore, the presence of these genes is responsible for iPSC-derived teratomas. Similar to iPSC, P19 teratocarcinoma cell line also has characteristics of embryonic carcinoma cells and the ability to differentiate into many cell types. We separately silenced the transcription factors Oct4, Sox2, Klf4, c-Myc and Nanog in P19 cells and measured the impact of this silencing in vivo. All silenced cells generated tumors when injected in immunosuppressed mice, but silencing of Oct4, Sox2 and Klf4 generated mainly teratomas with mesoderm tissue. Our results suggest that downregulation of these transcription factors is not enough to avoid the formation of teratomas, but their silencing affect their differentiation potential.

Objective To evaluate the presence of white matter and hemorrhagic lesions in brain MRI of children and adolescents with Fabry disease (FD). Methods Brain MRI studies in 44 consecutive children and teenagers (20 boys, mean age 14.6 years, range 7–21 years) were evaluated using classic sequences as well as, GRE-weighted images, for white matter lesions (WML) and chronic microbleed detection. All patients lacked history of stroke or TIA. Brain MRI findings in 46 consecutive children and adolescents without FD, referred for the evaluation of headaches (36 females, mean age 14.1 years, range 7–21 years) were evaluated as a control group. Additionally, we assessed the clinical manifestations of FD. Results Seven children (15.9%) with FD had brain MRI evidence of asymptomatic WML (5 girls, mean age 14.8 years, range: 13–20 years) compared with 3 children (6.5%) in the control group (p = 0.01). Brain abnormalities in patients with FD revealed WML, deep gray matter and infratentorial involvement. Three patients presented two lesions each. None of the children showed microbleeds. Regarding clinical manifestations, 90.9% of the patients had signs or symptoms of FD. Conclusion We identified asymptomatic white matter brain lesions in 15.9% of children with FD without clinical history of stroke. FD is a treatable disorder that should be routinely included in the differential diagnosis of both symptomatic and asymptomatic brain lesions in children and adolescents. The detection of brain lesions may foster earlier treatment.

Background: Pituitary adenomas can become invasive and aggressive, and in turn produce tumor recurrence. Endocan or endothelial cell specific molecule-1 (ESM1) has been associated with angiogenesis and tumor growth in gliomas, and lung, kidney, liver among other cancers, but there is a scarcity of information regarding its role in pituitary adenomas. In the search for biomarkers of tumor behavior our objective was to determine the relationship between endocan (ESM1) mRNA expression and cavernous sinus invasion, and its association with gene expression of VEGF, FGF2 and PDGF angiogenic factors in human pituitary adenomas.Methods: ESM1, VEGF, FGF2 and PDGF expression was determined by qRT-PCR in 28 pituitary tumor samples and tumor invasion was determined by the Knosp grade classification. Results were associated with clinical data. Results: We found that ESM1 was expressed in 75% of the tumors. FGF2 expression was higher in ESM1-positive compared to ESM1-negative tumors, and a significant negative correlation in the expression of FGF2 and PDGF was found. Although ESM1 expression did not show any differences in invasive and non-invasive tumors, a positive correlation between ESM1 and Knosp grade was reached when grade 0-3 tumors were considered, suggesting its participation in the initial periods of tumor invasion. Finally, no difference in ESM1 expression was found between functioning and non-functioning adenomas, or patients age. Conclusions: Our study points to a precise pattern of angiogenic factor expression in pituitary tumors, and its relation to invasive behavior, which should be considered in the tailoring of drug treatments for aggressive and resistant pituitary adenomas.

Cell death experiments are routinely done in many labs around the world, these experiments are the backbone of many assays for drug development. Cell death detection is usually performed in many ways, and requires time and reagents. However, cell death is preceded by slight morphological changes in cell shape and texture. In this paper, we trained a neural network to classify cells undergoing cell death. We found that the network was able to highly predict cell death after one hour of exposure to camptothecin. Moreover, this prediction largely outperforms human ability. Finally, we provide a simple python tool that can broadly be used to detect cell death.

Fil: Duarte Abritta, Bárbara. Instituto de Neurociencias. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Consejo Nacional de Investigaciones Científicas y Técnicas. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Duarte Abritta, Bárbara. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Sánchez, Stella Maris. Instituto de Neurociencias. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Consejo Nacional de Investigaciones Científicas y Técnicas. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Sánchez, Stella Maris. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Sánchez, Stella Maris. Universidad de Buenos Aires. Facultad de Cs. Exactas y Naturales. Departamento de Física; Argentina Fil: Abulafia, Carolina Andrea. Instituto de Neurociencias. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Consejo Nacional de Investigaciones Científicas y Técnicas. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Abulafia, Carolina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Abulafia, Carolina Andrea. Pontificia Universidad Católica Argentina. Instituto de Investigaciones Biomédicas; Argentina Fil: Gustafson, Deborah R. State University of New York University Downstate Health Sciences University. Department of Neurology; Estados Unidos Fil: Vázquez, Silvia. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Centro de imágenes moleculares; Argentina Fil: Sevlever, Gustavo. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Departamento de Neuropatología y Biología Molecular; Argentina Fil: Castro, Mariana N. Instituto de Neurociencias. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Consejo Nacional de Investigaciones Científicas y Técnicas. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Castro, Mariana N. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Castro, Mariana N. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; Argentina Fil: Castro, Mariana N. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Servicio de Psiquiatría; Argentina Fil: Fiorentini, Leticia. Instituto de Neurociencias. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Consejo Nacional de Investigaciones Científicas y Técnicas. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Fiorentini, Leticia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Fiorentini, Leticia. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Servicio de Psiquiatría; Argentina Fil: Villarreal, Mirta F. Instituto de Neurociencias. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Consejo Nacional de Investigaciones Científicas y Técnicas. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Villarreal, Mirta F. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Villarreal, Mirta F. Universidad de Buenos Aires. Facultad de Cs. Exactas y Naturales. Departamento de Física; Argentina Fil: Guinjoan, Salvador M. Instituto de Neurociencias. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Consejo Nacional de Investigaciones Científicas y Técnicas. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Guinjoan, Salvador M. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Guinjoan, Salvador M. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Fisiología; Argentina Fil: Guinjoan, Salvador M. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; Argentina Fil: Guinjoan, Salvador M. Universidad de Buenos Aires. Facultad de Psicología. Neurofisiología I; Argentina Fil: Guinjoan, Salvador M. Laureate Institute for Brain Research; Estados Unidos Abstract: A traditional hallmark of cognitive impairment associated with late-onset Alzheimer´s disease (LOAD) is episodic memory impairment. However, early alterations have been identified in brain regions associated with executive function in asymptomatic, middle-age offspring of patients with LOAD (O-LOAD) compared to those with no family history. We hypothesized that executive function among O-LOAD would correlate with structural and amyloid brain imaging differently from those without a family history of LOAD (control subjects, CS). Executive function, cortical thickness, and in-vivo Aβ deposits were quantified in 30 O-LOAD and 25 CS. Associations were observed among O-LOAD only. Cortical thickness in the left lateral orbitofrontal cortex was positively associated with Design Fluency. The Stroop Color and Word Test, correlated positively with right rostral mid-frontal cortex thickness. Trails Making Test-B was inversely related to left medial orbitofrontal thickness. Tower of London total time was positively associated with β-amyloid deposition in the right precuneus. These results support previous evidence that early executive dysfunction might reflect subtle, early changes in persons at risk of LOAD and suggests that executive function alterations deserve further exploration in the LOAD literature.

Human pluripotent stem cells (hPSCs), like embryonic (hESCs) and induced pluripotent stem cells (hiPSCs), exhibit an unusual cell cycle structure characterized by a short G1 phase and cells being most of time in S phase. hPSCs are receptive to differentiation cues during their transition through G1 phase when lineage determination is decided. Although several MicroRNAs (miRNAs) have been shown to target transcripts that directly or indirectly coordinate the cell cycle of pluripotent cells, its temporal expression profile along hPSCs cell cycle remains poorly characterized. miR-145 and miR-296 are induced during differentiation and silence the self-renewal and pluripotency program. miR-302 family is essential for hPSCs stemness and its expression decreases during differentiation. We aimed to study how the aforementioned miRNAs are regulated along the cell cycle of hPSCs. We demonstrated by pharmacological synchronization and block and release experiments that miR-145, miR-296 and miR-302 family are periodically expressed in hPSCs. Importantly, miR-302 family expression is induced at G1/S boundary and remained high at S phase, presumably to impede differentiation onset. Besides, we confirmed by a gene ontology analysis that many validated miR-302 family target genes are involved in cell cycle regulation.

Background and purpose There are instances in which an estimate of the brain volume should be obtained from MRI in clinical practice. Our objective is to calculate cross-sectional robustness of a convolutional neural network (CNN) based software (Entelai Pic) for brain volume estimation and compare it to traditional software such as FreeSurfer, CAT12 and FSL in healthy controls (HC). Materials and Methods Sixteen HC were scanned four times, two different days on two different MRI scanners (1.5 T and 3 T). Volumetric T1-weighted images were acquired and post-processed with FreeSurfer v6.0.0, Entelai Pic v2, CAT12 v12.5 and FSL v5.0.9. Whole-brain, grey matter (GM), white matter (WM) and cerebrospinal fluid (CSF) volumes were calculated. Correlation and agreement between methods was assessed using intraclass correlation coefficient (ICC) and Bland Altman plots. Robustness was assessed using the coefficient of variation (CV). Results Whole-brain volume estimation had better correlation between FreeSurfer and Entelai Pic (ICC (95% CI) 0.96 (0.94−0.97)) than FreeSurfer and CAT12 (0.92 (0.88−0.96)) and FSL (0.87 (0.79−0.91)). WM, GM and CSF showed a similar trend. Compared to FreeSurfer, Entelai Pic provided similarly robust segmentations of brain volumes both on same-scanner (mean CV 1.07, range 0.20–3.13% vs. mean CV 1.05, range 0.21–3.20%, p = 0.86) and on different-scanner variables (mean CV 3.84, range 2.49–5.91% vs. mean CV 3.84, range 2.62–5.13%, p = 0.96). Mean post-processing times were 480, 5, 40 and 5 min for FreeSurfer, Entelai Pic, CAT12 and FSL respectively. Conclusion Based on robustness and processing times, our CNN-based model is suitable for cross-sectional volumetry on clinical practice.

Objective: Increased life expectancy and exponential growth of adults suffering from Alzheimer's disease (AD) worldwide, has led to biomarkers incorporation for diagnosis in early stages. Use of neuropsychological testing remains limited. This study aimed to identify which neuropsychological tests best indicated underlying AD pathophysiology.Methods: One hundred and forty-one patients with MCI (Mild Cognitive Impairment) were studied. A neuropsychological test battery based on the Uniform Data Set (UDS) from the Alzheimer's Disease Centers program of the National Institute on Aging (NIA) was performed and amyloid markers recorded; according to presence or absence of amyloid identified by positive PIB-PET findings, or low CSF Aβ42 levels, patients were separated into MCI amyloid-(n:58) and MCI amyloid + (n = 83) cases.Results: Statistical differences were found in all memory tests between groups. Delayed recall score at thirty minutes on the Rey Auditory Verbal Learning Test (AVLT) was the best predictor of amyloid pathology presence (AUC 0.68), followed by AVLT total learning (AUC 0.66) and AVLT Recognition (AUC 0.59) scores, providing useful cut off values in the clinical setting.Conclusions: Use of neuropsychological testing, specifically AVLT scores with cutoff values, contributed to the correct diagnosis of MCI due to AD in this SouthAmerican cohort

Fil: Sánchez, Stella M. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Sánchez, Stella M. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Sánchez, Stella M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; Argentina Fil: Duarte-Abritta, Bárbara. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Duarte-Abritta, Bárbara. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Abulafia, Carolina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Abulafia, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Abulafia, Carolina. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: De Pino, Gabriela. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: De Pino, Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: De Pino, Gabriela. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología; Argentina Fil: De Pino, Gabriela. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Departamento de Imágenes. Laboratorio de Neuroimágenes; Argentina Fil: Bocaccio, Hernan. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Bocaccio, Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Bocaccio, Hernan. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; Argentina Fil: Castro, Mariana N. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Castro, Mariana N. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Castro, Mariana N. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Fisiología; Argentina Fil: Castro, Mariana N. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; Argentina Fil: Sevlever, Gustavo. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Departamento de Neuropatología y Biología Molecular; Argentina Fil: Fonzo, Greg A. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Departamento de Neuropatología y Biología Molecular; Argentina Fil: Nemeroff, Charles B. University of Texas at Austin. Department of Psychiatry. Institute of Early Life Adversity Research; Estados Unidos Fil: Gustafson, Deborah R. State University of New York. University Downstate Medical Center. Department of Neurology; Estados Unidos Fil: Gustafson, Deborah R. University of Skövde. Department of Health and Education; Suecia Fil: Guinjoan, Salvador M. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Guinjoan, Salvador M. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Guinjoan, Salvador M. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Fisiología; Argentina Fil: Guinjoan, Salvador M. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; Argentina Fil: Guinjoan, Salvador M. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Servicio de Psiquiatría; Argentina Fil: Guinjoan, Salvador M. Universidad de Buenos Aires. Facultad de Psicología. Neurofisiología I; Argentina Fil: Villarreal, Mirta F. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Villarreal, Mirta F. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Villarreal, Mirta F. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; Argentina Abstract: Tau accumulation affecting white matter tracts is an early neuropathological feature of late-onset Alzheimer’s disease (LOAD). There is a need to ascertain methods for the detection of early LOAD features to help with disease prevention efforts. The microstructure of these tracts and anatomical brain connectivity can be assessed by analyzing diffusion MRI (dMRI) data. Considering that family history increases the risk of developing LOAD, we explored the microstructure of white matter through dMRI in 23 cognitively normal adults who are offspring of patients with Late-Onset Alzheimer’s Disease (O-LOAD) and 22 control subjects (CS) without family history of AD. We also evaluated the relation of white matter microstructure metrics with cortical thickness, volumetry, in vivo amyloid deposition (with the help of PiB positron emission tomography -PiB-PET) and regional brain metabolism (as FDG-PET) measures. Finally we studied the association between cognitive performance and white matter microstructure metrics. O-LOAD exhibited lower fiber density and fractional anisotropy in the posterior portion of the corpus callosum and right fornix when compared to CS. Among O-LOAD, reduced fiber density was associated with lower amyloid deposition in the right hippocampus, and greater cortical thickness in the left precuneus, while higher mean diffusivity was related with greater cortical thickness of the right superior temporal gyrus. Additionally, compromised white matter microstructure was associated with poorer semantic fluency. In conclusion, white matter microstructure metrics may reveal early differences in O-LOAD by virtue of parental history of the disorder, when compared to CS without a family history of LOAD. We demonstrate that these differences are associated with lower fiber density in the posterior portion of the corpus callosum and the right fornix.

Alzheimer's disease is the most frequent cause of cognitive disorders and dementia in older adults and is considered a new epi- demic. Due to its different cognitive, behavioral and functional manifestations, the detection, and diagnosis of patients with Alzheimer's Disease Dementia can represent a challenge. In this Clinical Practice Recommendation, management are given with levels based on the best scientific evidence available. Likewise, indications for study, or referral to a higher level of sanitary assistance are presented, according to the complexity of each clinical case. In this way, a set of practical recommendations of support is provided for decision making by health professionals at each sanitary level, from primary care to medical specialists. Through an operational and dynamic approach, this recommendations propose a global strategy based on evidence for patients, family members and health agents involved in this pathology, of great social relevance.

Human embryonic and induced pluripotent stem cells (hESCs and hiPSCs) are self-renewing human pluripotent stem cells (hPSCs) that can differentiate to a wide range of specialized cells. Notably, hPSCs enhance their undifferentiated state and self-renewal properties in hypoxia (5% O2). Although thoroughly analyzed, hypoxia implication in hPSCs death is not fully determined. In order to evaluate the effect of chemically mimicked hypoxia on hPSCs cell survival, we analyzed changes in cell viability and several aspects of apoptosis triggered by CoCl2 and dimethyloxalylglycine (DMOG). Mitochondrial function assays revealed a decrease in cell viability at 24 h post-treatments. Moreover, we detected chromatin condensation, DNA fragmentation and CASPASE-9 and 3 cleavages. In this context, we observed that P53, BNIP-3, and NOXA protein expression levels were significantly up-regulated at different time points upon chemical hypoxia induction. However, only siRNA-mediated downregulation of NOXA but not HIF-1α, HIF-2α, BNIP-3, and P53 did significantly affect the extent of cell death triggered by CoCl2 and DMOG in hPSCs. In conclusion, chemically mimicked hypoxia induces hPSCs cell death by a NOXA-mediated HIF-1α and HIF-2α independent mechanism.

Introduction Mutations in presenilin-1 (PSEN1) account for the majority of cases of familial autosomal dominant early-onset Alzheimer's disease (AD) as well as in sporadic forms. Atypical presentations are reported including extrapyramidal signs. In the last years, a pleiotropic effect of some PSEN1 variants has been reported in Parkinson's disease (PD). Objective to report a new PSEN1 mutation characterized by early-onset Parkinsonism (EOPD) without dementia or classical AD biomarkers phenotype. Patient and methods An Argentinian 46 years old woman was diagnosed with EOPD at 35 years old with no family history of neurodegenerative disorders. Her medical history included iron deficiency and anemia since childhood. A brain MRI showed moderate frontal atrophy. 18FDG-PET and PiB-PET as well as CSF biomarkers were inconclusive for AD. Two neuropsychological examinations were compatible with a mild non amnestic cognitive impairment. Whole blood DNA was extracted and whole exome sequencing and analysis was performed. Results and conclusion A heterozygous novel missense PSEN1 mutation (position 14:73637540, A > T, pArg41Ser) was identified as a likely causative mutation in this patient. To the best of our knowledge, this case is the first PSEN1 mutation with a l -dopa responsive Parkinsonism lacking distinctive classical AD biomarkers. This case opens a new window to explore the pathophysiological link among PSEN1 and EOPDs and contributes to increase the phenotypes of PSEN1 variants.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the presence of misfolded proteins, amyloid-β (Aβ) aggregates, and neuroinflammation in the brain. Microglial cells are key players in the context of AD, being capable of releasing cytokines in response to Aβ and degrading aggregated proteins by mechanisms involving the ubiquitin-proteasome system and autophagy. Here, we present in vivo and in vitro evidence showing that microglial autophagy is affected during AD progression. PDAPPJ20 mice—murine model of AD—exhibited an accumulation of the autophagy receptor p62 and ubiquitin+ aggregates in Iba1+ microglial cells close to amyloid deposits in the hippocampus. Moreover, cultured microglial BV-2 cells showed an enhanced autophagic flux during a 2-h exposure to fibrillar Aβ, which was decreased if the exposure was prolonged to 24 h, a condition analogous to the chronic exposure to Aβ in the human pathology. The autophagic impairment was also associated with lysosomal damage, depicted by membrane permeabilization as shown by the presence of the acid hydrolase cathepsin-D in cytoplasm and altered LysoTracker staining. These results are compatible with microglial exhaustion caused by proinflammatory conditions and persistent exposure to aggregated Aβ peptides. In addition, we found LC3- positive autophagic vesicles accumulated in phagocytic CD68+ microglia in human AD brain samples, suggesting defective autophagy in microglia of AD brain. Our results indicate that the capacity of microglia to degrade Aβ and potentially other proteins through autophagy may be negatively affected as the disease progresses. Preserving autophagy in microglia thus emerges as a promising approach for treating AD. Fil: Pomilio, Carlos Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Gorojod, Roxana Mayra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Riudavets, Miguel Angel. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; Argentina Fil: Vinuesa, María Angeles. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Presa, Jessica Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Gregosa Merlino, Amal Patricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Bentivegna, Melisa Inés María. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Alaimo, Agustina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Porte Alcon, Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Sevlever, Gustavo. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; Argentina Fil: Kotler, Monica Lidia. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Beauquis, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Saravia, Flavia Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Purpose To describe results of the Amyloid, Tau, Neurodegeneration (ATN) research framework classification in the Argentine‐Alzheimer's Disease Neuroimaging Initiative (arg‐ADNI) cohort. Methods Twenty‐three patients with mild cognitive impairment (MCI), 12 dementia of Alzheimer's type (DAT), and 14 normal controls were studied following the ADNI2 protocol. Patients were categorized according to presence or absence of the biomarkers for amyloid beta (Aβ; A: amyloid positron emission tomography [PET] scan or cerebrospinal fluid [CSF] Aβ42), tau (T: CSF phosphorylated‐tau), and neurodegeneration (N: CSF total‐tau, fluorodeoxyglucose [FDG]‐PET scan, or structural magnetic resonance imaging [MRI] scan). Results A+T+N+ biomarker profile was identified at baseline in 91% of mild dementia patients, 20% of early MCI patients, 46% of late MCI patients, and 14% of control subjects. Suspected non‐AD pathophysiology (SNAP, A‐T‐N+) was found in 8% of mild dementia, 20% of early MCI, 15% of late MCI, and 7% of control subjects. Conversion rates to dementia after 5‐year follow‐up were 85% in A+T+N+ MCI patients and 50% in A‐T‐N+ patients. Conclusions We present initial 5‐year follow‐up results of a regional ADNI based on AD biomarkers and the ATN classification.

There is an urgent need for an improved understanding of the relationship between repetitive sports concussion and cognitivedecline risk. The Argentina- Sports Concussion Assessment & Research Study (Arg-SCARS) explores the link between repetitivesports concussion and cognitive function decline in rugby players. Its objective is to describe the study design and the preliminary results concerning clinical profiles of rugby players following sports concussion. The current paper is a descriptive study of select characteristics and clinical symptoms identified from concussed athletes within 72 h after the injury. The 92 participants had an average age of 22.64 years and had been playing rugby for a mean of 14.72 years. 66.3% had history of concussions, with an average number of clinical concussions of 1.94. The mean of symptoms reported on Post-Concussion Symptoms Scale was 5.41. The mean symptom severity score was 14.49. Acute concussion symptoms, Beck’s Depression Inventory and attentional composite score were significantly predictive of symptoms within the first 72h following concussion. As conclusions it was possible to recognize the full spectrum of post-concussion related situations is essential to monitor recovery and tailor interventions for specific cases. Arg-SCARS’s findings will help understand the influence of repetitive head trauma in the progress of neurological damage in athletes.

Fil: Wilsona, Kathleen E. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Abulafia, Carolina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Abulafia, Carolina. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Cronofisiología; Argentina Fil: Abulafia, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Loewensteind, David A. University of Miami. Miller School of Medicine. Department of Psychiatry and Behavioral Sciences and Center on Aging; Estados Unidos Fil: Vigo, Daniel Eduardo. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Cronofisiología; Argentina Fil: Vigo, Daniel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Sevlevere, Gustavo. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Departamento de Neuropatología y Biología Molecular; Argentina Fil: Nemeroffd, Charles B. University of Miami. Miller School of Medicine. Department of Psychiatry and Behavioral Sciences and Center on Aging; Estados Unidos Fil: Mirta F. Villarreal. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Mirta F. Villarreal. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Mirta F. Villarreal. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; Argentina Fil: Guinjoan, Salvador M. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Guinjoan, Salvador M. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Guinjoan, Salvador M. Universidad de Buenos Aires. Departamento de Psiquiatría y Salud Mental. Unidad docente Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina Fil: Guinjoan, Salvador M. Universidad de Buenos Aires. Facultad de Psicología. Departamento de Neurofisiología; Argentina Fil: Guinjoan, Salvador M. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Servicio de Psiquiatría; Argentina Abstract: The main objective of this study was to assess cognitive and depressive manifestations associated with Alzheimer’s disease in middle-aged asymptomatic individuals with maternal versus paternal family history of the disease using standardly used neuropsychological measures and a novel cognitive stress test, the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L). We evaluated cognitive abilities in offspring of late-onset Alzheimer’s disease patients and a control group with no family history of dementia. Results showed lower cognitive performance in verbal episodic memory and semantic memory in participants with an Alzheimer’s parent, especially in individuals with a maternal family history of the disease. While the standardly used neuropsychological evaluations were sensitive to differences in cognition between those with a maternal history of the disease and the control group, the LASSI-L was sensitive to proactive semantic interference impairments in both groups with a paternal and maternal family history of the disease. Depressive symptoms may affect cognitive performance differently in individuals with a family history of Alzheimer’s disease compared to a control group, especially in individuals with a maternal history of the disease. This study highlights the value of semantic interference paradigms in early detection of Alzheimer’s and emphasizes the importance of studying maternal versus paternal transmission of the disease.