The first genome-wide association study in the Argentinian and Chilean populations identifies shared genetics with Europeans in Alzheimer's disease.

INTRODUCTION: Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities. METHODS: We performed GWAS on sporadic Alzheimer's disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the European Alzheimer and Dementia Biobank (EADB) in a meta-analysis and tested their genetic risk score (GRS) performance in this admixed population. RESULTS: We detected apolipoprotein E ε4 as the single genome-wide significant signal (odds ratio  = 2.93 [2.37-3.63], P = 2.6 × 10-23 ). The meta-analysis with EADB summary statistics revealed four new loci reaching GWAS significance. Functional annotations of these loci implicated endosome/lysosomal function. Finally, the AD-GRS presented a similar performance in these populations, despite the score diminished when the Native American ancestry rose. DISCUSSION: We report the first GWAS on AD in a population from South America. It shows shared genetics modulating AD risk between the European and these admixed populations. HIGHLIGHTS: This is the first genome-wide association study on Alzheimer's disease (AD) in a population sample from Argentina and Chile. Trans-ethnic meta-analysis reveals four new loci involving lysosomal function in AD. This is the first independent replication for TREM2L, IGH-gene-cluster, and ADAM17 loci. A genetic risk score (GRS) developed in Europeans performed well in this population. The higher the Native American ancestry the lower the GRS values.

Comparison of complications and reoperations in AO/OTA 43.C3 pilon fractures treated with conventional ORIF versus minimally invasive hexapod ring fixation.

INTRODUCTION: Controversy exists regarding the optimal management of AO/OTA 43. C3 pilon fractures. Open reduction and internal fixation (ORIF) is the gold standard treatment, but serious soft tissue and infectious complications have been previously reported. Minimally invasive strategies using hexapod ring fixation (HRF) with supplemental limited internal fixation have been used to reduce the incidence of complications. Previous studies have included heterogeneous types of pilon fractures, with non-comminuted injuries being more likely to be treated with ORIF and complex fractures receiving HRF treatment. To our knowledge, no studies have compared the complications and reoperation rates between ORIF and HRF exclusively for C3 fractures. METHODS: Retrospective study comparing 53 patients treated for AO/OTA 43.C3 pilon fracture with ORIF or HRF in a trauma level I center with at least a two-year follow-up. Patients treated between January 2015 and January 2019 received ORIF and those treated between January 2019 and January 2021 received HRF. Complications were divided into two groups: minor (superficial infection and malalignment) and major (non-union, deep infection, and amputation). Reoperations, prevalence of ankle osteoarthritis, and requirement for ankle arthrodesis/total ankle replacement were registered. RESULTS: We included 30 and 23 patients in the ORIF and HRF groups, respectively. The overall complication rate was similar in both groups, with 50% and 56,5% of the patients having complications in the ORIF and HRF groups, respectively (p:0,63). Minor complications were significantly more prevalent in the HRF group (p<0,001) whilst the ORIF group had a significantly higher rate of major complications (p<0,01). Superficial infections were highly prevalent in the HRF group (47,8%), as they were related to half-pin or K-wire infections. Deep infection was present only in the ORIF group, with 20% of the patients developing this major complication (p:0,03). Non-union rate, reoperations, ankle osteoarthritis, and the need for arthrodesis or ankle replacement showed no significant differences. CONCLUSION: In AO/OTA 43.C3 fractures, HRF is safe and effective, achieving high union rates with a significantly lower rate of major complications compared to ORIF. According to our results, ORIF should be used cautiously for these types of fractures, considering the increased risk of deep infection.

Treatment of Severe Rigid Posttraumatic Equinus Deformity With Gradual Deformity Correction and Arthroscopic Ankle Arthrodesis.

BACKGROUND: Posttraumatic ankle equinus is associated with rigid deformity, poor skin condition, and multiple prior surgeries. Open acute correction has been described using osteotomies, talectomy, and arthrodesis, but concerns exist about skin complications, neurologic alterations, secondary limb discrepancy, and bone loss. Gradual correction using a multiplanar ring fixator and arthroscopic ankle arthrodesis (AAA) may decrease these complications. METHODS: We retrospectively reviewed patients undergoing correction of posttraumatic rigid equinus with at least 1 year of follow-up after frame removal. The procedure consisted of percutaneous Achilles lengthening, gradual equinus correction using a multiplanar ring fixator, and AAA retaining the fixator in compression with screw augmentation. Frame removal depended on signs of union on the computed tomography scan. Visual analog scale (VAS) and Foot Function Index (FFI) scores were assessed as well as preoperative and postoperative x-rays. Complications were noted throughout the follow-up period. RESULTS: Five patients were treated with a mean age of 35 years and mean follow-up of 31 months. Deformities were gradually corrected into a plantigrade foot over an average duration of 6 weeks. Union was achieved in all patients with a mean time of an additional 25 weeks, for a mean total frame time of 31 weeks. The mean preoperative tibiotalar angle was 151 degrees and was corrected to 115 degrees. FFI score improved from a mean of 87 to 24 and VAS from 8 to 2. CONCLUSION: Posttraumatic rigid equinus can be treated effectively using gradual correction followed by integrated AAA in a safe and reproducible manner. Patients in this series had excellent functional, radiological, and satisfaction results. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Interventional Study to Evaluate the Clinical Effects and Safety of the Nutraceutical Compound BrainUp-10® in a Cohort of Patients with Alzheimer's Disease: A Multicenter, Randomized, Double-Blind, and Placebo-Controlled Trial.

BACKGROUND: Clinically-evaluated nutraceuticals are candidates for Alzheimer's disease (AD) prevention and treatment. Phase I studies showed biological safety of the nutraceutical BrainUp-10®, while a pilot trial demonstrated efficacy for treatment. Cell studies demonstrated neuroprotection. BrainUp-10® blocks tau self-assembly. Apathy is the most common of behavioral alterations. OBJECTIVE: The aim was to explore efficacy of BrainUp-10® in mitigating cognitive and behavioral symptoms and in providing life quality, in a cohort of Chilean patients with mild to moderate AD. METHODS: The was a multicenter, randomized, double blind, placebo-controlled phase II clinical study in mild to moderate AD patients treated with BrainUp-10® daily, while controls received a placebo. Primary endpoint was Apathy (AES scale), while secondary endpoints included Mini-Mental State Examination (MMSE), Trail Making Test (TMT A and TMT B), and Neuropsychiatry Index (NPI). AD blood biomarkers were analyzed. Laboratory tests were applied to all subjects. RESULTS: 82 patients were enrolled. The MMSE score improved significantly at week 24 compared to baseline with tendency to increase, which met the pre-defined superiority criteria. NPI scores improved, the same for caregiver distress at 12th week (p = 0.0557), and the alimentary response (p = 0.0333). Apathy tests showed a statistically significant decrease in group treated with BrainUp-10®, with p = 0.0321 at week 4 and p = 0.0480 at week 12 treatment. A marked decrease in homocysteine was shown with BrainUp-10® (p = 0.0222). CONCLUSION: Data show that BrainUp-10® produces a statistically significant improvement in apathy, ameliorating neuropsychiatric distress of patients. There were no compound-related adverse events. BrainUp-10® technology may enable patients to receive the benefits for their cognitive and behavioral problems.

Dementia in Latin America: Paving the way toward a regional action plan.

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF.

Biomarkers for Alzheimer's Disease.

Alzheimer´s disease (AD) and related forms of dementia are increasingly affecting the aging population throughout the world, at an alarming rate. The World Alzheimer´s Report indicates a prevalence of 46.8 million people affected by AD worldwide. As population ages, this number is projected to triple by 2050 unless effective interventions are developed and implemented. Urgent efforts are required for an early detection of this disease. The ultimate goal is the identification of viable targets for the development of molecular markers and validation of their use for early diagnosis of AD that may improve treatment and the disease outcome in patients. The diagnosis of AD has been difficult to resolve since approaches for early and accurate detection and follow-up of AD patients at the clinical level have been reported only recently. Some proposed AD biomarkers include the detection of pathophysiological processes in the brain in vivo with new imaging techniques and novel PET ligands, and the determination of pathogenic proteins in cerebrospinal fluid showing anomalous levels of hyperphosphorylated tau and low Aß peptide. These biomarkers have been increasingly accepted by AD diagnostic criteria and are important tools for the design of clinical trials, but difficulties in accessibility to costly and invasive procedures have not been completely addressed in clinical settings. New biomarkers are currently being developed to allow determinations of multiple pathological processes including neuroinflammation, synaptic dysfunction, metabolic impairment, protein aggregation and neurodegeneration. Highly specific and sensitive blood biomarkers, using less-invasive procedures to detect AD, are derived from the discoveries of peripheric tau oligomers and amyloid variants in human plasma and platelets. We have also developed a blood tau biomarker that correlates with a cognitive decline and also with neuroimaging determinations of brain atrophy.

Frequency of frailty and its association with cognitive status and survival in older Chileans.

BACKGROUND: Age-associated brain physiologic decline and reduced mobility are key elements of increased age-associated vulnerability. OBJECTIVE: To study the frequency of frailty phenotype and its association with mental health and survival in older Chileans. METHODS: Follow-up of ALEXANDROS cohorts designed to study disability associated with obesity in community-dwelling people 60 years and older living in Santiago, Chile. At baseline, 2,098 (67% women) of 2,372 participants had the necessary measurements for the identification of the frailty phenotype: weak handgrip dynamometry, unintentional weight loss, fatigue/exhaustion, five chair-stands/slow walking speed and difficulty walking (low physical activity). After 10-15 years, 1,298 people were evaluated and 373 had died. Information regarding deaths was available for the whole sample. RESULTS: The prevalence of frailty at baseline (≥3 criteria) in the whole sample was 13.9% (women 16.4%; men 8.7%) and the pre-frailty prevalence (1-2 criteria) was 63.8% (65.0% vs 61.4%), respectively. Frailty was associated with cognitive impairment (frail 48.1%; pre-frail 21.7%; nonfrail 20.5%, P<0.001) and depression (frail 55.1%; pre-frail 27.3%; nonfrail 18.8%, P<0.001). Logistic regression models for frailty adjusted for sex and age showed a strong association between frailty and mild cognitive impairment (MCI) (odds ratio [OR] =3.93; 95% CI: 1.41-10.92). Furthermore, an important association was found for depression and frailty (OR =2.36; 95% CI 1.82-3.06). Age- and sex-adjusted hazard ratios (HRs) for death showed an increased risk with increasing frailty: pre-frail HR =1.56 (95% CI: 1.07-2.29), frail HR =1.91 (95% CI: 1.15-3.19); after adjustment by age and sex, a higher risk of death was observed for people identified as frail (HR =1.56, P=0.014) and pre-frail (HR =1.30, P=0.065). MCI and dementia were also risk factors for death (MCI: HR =1.69, P<0.027; dementia: HR =1.66, P=0.016). CONCLUSION: Frailty is highly prevalent and strongly associated with cognitive impairment and depression in older Chileans. The risk for death was higher for frail people, but underlying cognitive impairment is a key component of the lower survival rate.

Anatomical variations of the foramen transversarium in cervical vertebrae / Variaciones anatómicas del foramen transverso en vértebras cervicales

The cervical vertebrae are recognized mainly by the presence of the foramen transversarium, which is crossed by the vertebral artery and vein, accompanied by sympathetic fibers. The main objective of this study was to observe and describe the anatomy and variations in the foramen transversarium. 121 cervical vertebrae were analyzed, including the macroscopic characteristics, shape and diameter and presence of the foramen transversarium, as well as the accessory foramen transversarium. All cervical vertebrae presented the foramen transversarium, with a mean diameter of 5.60 mm and a mean diameter of 4.40 mm on the right and 5.92 mm - 5.56 mm on the left, respectively. With regard to shape classification according to Taitz et al. (1978), 90.08 % presented the same shape on both sides, and 9.91 % had different shapes. The presentation of the different shapes was as follows: shape 1 41.32 %; shape 2 4.13 %; shape 3 18.8 %; shape 4 14.04 %; and shape 5 12.39 %. Regarding the presence of accessory foramen transversarium, 17.35 % of the vertebrae presented it, 66.6 % unilateral, 57.14 % on the right side and 42.85 % on the left side. Osteophytes, were presented in 5.7 %. The anatomical knowledge of these variations is useful for spine surgeons in preoperative planning and for preventing vertebral vessel and sympathetic nerve injuries during cervical surgical approaches.

Las vértebras cervicales son reconocidas principalmente por la presencia del foramen transverso (FT), por el cual transita la arteria y vena vertebral además de fibras simpáticas. Las variaciones en el FT pueden estar asociadas con una alteración en el calibre y el curso de la arteria vertebral. El objetivo del presente estudio fue observar y describir la anatomía así como las variaciones en el FT. Fueron analizadas 121 vértebras cervicales, en las cuales el FT fue observado macroscópicamente de manera bilateral así como el foramen transverso accesorio (FTA) en las que se encontrara presente. La forma y diámetros máximo y mínimo del FT fue medido de manera bilateral con ayuda de un cáliper digital. De 121 vértebras cervicales, la totalidad presentaron FT con diámetros máximo y mínimo derecho de 5,60 y 4,40 mm respectivamente y de 5,92 y 5,56 mm máximo y mínimo del lado izquierdo. Con respecto a la clasificación de forma de Taitz et al. (1978) el 90,08 % presentó la misma forma de manera bilateral y un 9,91% formas distintas. La forma 1 se presentó en un 41,32 %, la 2 en un 4,13 %, forma 3 18,8 %, 4 14,04 % y 5 en 12,39 %. Con respecto a la presencia de FTA, un 17,35 % lo presentó, siendo 66,6 % unilaterales, un 57,14 % derecho y 42,85 % izquierdo. La anatomía y variaciones en el FT y la arteria vertebral y los componentes nerviosos están interrelacionados. Su conocimiento morfológico es clínicamente importante, ya que el curso de la arteria vertebral puede distorsionarse en tales situaciones. Por lo que es importante a la hora de adoptar medidas cautelares para salvaguardar la arteria vertebral en las cirugías de columna cervical.

Low Leptin Availability as a Risk Factor for Dementia in Chilean Older People.

OBJECTIVE: The aim was to study the role of leptin in the development of dementia. METHODS: Follow-up of the ALEXANDROS cohorts, with baseline measurements in 2000. From 1,136 available subjects free of dementia at baseline, 667 subjects had frozen baseline blood samples for measuring leptin and soluble leptin receptor (sOB-R). The free leptin index (FLI) was calculated as the ratio of leptin to sOB-R. Dementia was defined as an MMSE score <22 and a score >5 in the Pfeffer Activities Questionnaire. RESULTS: After 15 years of follow-up, 42 incident cases of dementia were identified. No difference in serum leptin was observed between people with and without dementia, but sOB-R was higher in demented than in nondemented subjects (sOB-R: 44.94 ± 23.97 vs. 33.73 ± 21.13 ng/ml). The adjusted risk for dementia increased, the higher the log sOB (hazard ratio = 3.58; 95% CI 1.72-7.45, p = 0.001). CONCLUSION: Lower availability of free leptin was found in demented than in nondemented people, suggesting a role of leptin in cognition.

Reconstrucción de la pared abdominal mediante la técnica de separación de componentes / Component separation technique for the repair of abdominal wall defects

Antecedentes: La reconstrucción de la pared abdominal tiene como fin restaurar el soporte estructural, otorgando una cobertura estable y optimizando la apariencia estética. La técnica de separación de componentes consiste en el avance medial de un componente muscular y fascial inervados, para reconstruir defectos en la línea media, logra un cierre sin tensión y ayuda a recrear la dinámica de la pared abdominal. Objetivo: El objetivo del siguiente trabajo es presentar la experiencia del Hospital de Carabineros en la reconstrucción de tales defectos utilizando esta técnica y evaluar la tasa de recidiva. Material y método: Estudio retrospectivo de pacientes operados en el Hospital entre 2010 y 2015. Se describe la técnica quirúrgica utilizada.Resultados: Se presenta una serie de 6 pacientes operados en dicho período. El tamaño promedio del defecto fue 272,8 cm². Se utilizó la técnica clásica de separación de componentes y en algunos casos modificaciones para preservar perforantes. La cirugía tuvo una duración de 185 min en promedio. No se han presentado recidivas a la fecha entre los pacientes operados (seguimiento promedio 16,8 meses). Conclusiones: La técnica de separación de componentes repara defectos extensos de manera anatómica, autógena y devolviendo la funcionalidad a la pared abdominal. Es un procedimiento que no está libre de complicaciones, sin embargo, en nuestra experiencia los resultados son estables en el tiempo sin evidenciar recidivas. Se recomienda una adecuada evaluación y selección de cada caso.

Background: The component separation technique is a type of rectus abdominis muscle advancement flap that allows reconstruction of such large ventral defects. The advantages of the component separation technique are that it restores functional and structural integrity of the abdominal wall, provides stable soft tissue coverage, and optimizes aesthetic appearance. Aim: To report our experience in abdominal reconstruction using this technique. Material and methods: Review of medical records of 6 patients subjected to an abdominal wall repair using the component separation technique. Results: The mean size of the abdominal wall defect was 272.8 cm². The classic technique or a modification to preserve perforator vessels were used. The mean surgical time was 185 minutes. After a follow up of 16.8 months, no relapses were observed. Conclusions: In this experience the component separation technique had good results and no relapse of the defect was observed.

An update on aging and dementia in Chile / Atualização em envelhecimento e demência no Chile

Chile is in an advanced demographic transition stage with the population over 60 years of age representing 15% of the total population and whose number of elderly has more than doubled between 1990 and 2014. Rapid economic advancement has promoted significant changes in social organization to which the country is not accustomed. The mental health problems of the elderly are particularly challenging to the countrys present social and health structures. The prevalence of dementia in people over 60 years exceeds 8% and is even higher in the rural population. There is more training on dementia in the local medical and scientific community, increased awareness within the civilian community but insufficientresponsiveness from the state to the broad diagnostic and therapeutic requirements of patients and caregivers. The objective of the present study was to provide an update of the information on dementia in the context of the ageing process in Chile.

O Chile está num avançado estágio de transição epidemiológica, com a população de 60 anos ou mais representando 15% da população total e o número de idosos tem mais que dobrado entre 1990 e 2014. O rápido avanço econômico tem promovido significantes mudanças na organização social para as quais o país não está habituado. Os problemas de saúde mental em idosos são particularmente desafiadores para as estruturas sociais e de saúde atuais do país. A prevalência de demência entre aqueles com idade superior a 60 anos excede 8% e é mais elevada na população rural. Há mais treinamento em demência na população médica e comunidade científica locais, aumentando o conhecimento dentro da comunidade civil, porém, com insuficiente resposta do estado às necessidades diagnósticas e terapêuticas de pacientes e cuidadores. O objetivo deste estudo foi providenciar uma atualização da informação sobre demência no contexto de envelhecimento cerebral do Chile.

An update on aging and dementia in Chile.

Chile is in an advanced demographic transition stage with the population over 60 years of age representing 15% of the total population and whose number of elderly has more than doubled between 1990 and 2014. Rapid economic advancement has promoted significant changes in social organization to which the country is not accustomed. The mental health problems of the elderly are particularly challenging to the country's present social and health structures. The prevalence of dementia in people over 60 years exceeds 8% and is even higher in the rural population. There is more training on dementia in the local medical and scientific community, increased awareness within the civilian community but insufficient responsiveness from the state to the broad diagnostic and therapeutic requirements of patients and caregivers. The objective of the present study was to provide an update of the information on dementia in the context of the ageing process in Chile.

O Chile está num avançado estágio de transição epidemiológica, com a população de 60 anos ou mais representando 15% da população total e o número de idosos tem mais que dobrado entre 1990 e 2014. O rápido avanço econômico tem promovido significantes mudanças na organização social para as quais o país não está habituado. Os problemas de saúde mental em idosos são particularmente desafiadores para as estruturas sociais e de saúde atuais do país. A prevalência de demência entre aqueles com idade superior a 60 anos excede 8% e é mais elevada na população rural. Há mais treinamento em demência na população médica e comunidade científica locais, aumentando o conhecimento dentro da comunidade civil, porém, com insuficiente resposta do estado às necessidades diagnósticas e terapêuticas de pacientes e cuidadores. O objetivo deste estudo foi providenciar uma atualização da informação sobre demência no contexto de envelhecimento cerebral do Chile.

Can nutraceuticals prevent Alzheimer's disease? Potential therapeutic role of a formulation containing shilajit and complex B vitamins.

Alzheimer's disease (AD) is a brain disorder displaying a prevalence and impact in constant expansion. This expansive and epidemic behavior is concerning medical and public opinion while focusing efforts on its prevention and treatment. One important strategy to prevent this brain impairment is based on dietary changes and nutritional supplements, functional foods and nutraceuticals. In this review we discuss the potential contributions of shilajit and complex B vitamins to AD prevention. We analyze the status of biological studies and present data of a clinical trial developed in patients with mild AD. Studies suggest that shilajit and its active principle fulvic acid, as well as a formula of shilajit with B complex vitamins, emerge as novel nutraceutical with potential uses against this brain disorder.

Clinical diagnosis in preclinical stage of Alzheimer's disease.

Preclinical diagnosis of Alzheimer's disease using biomarkers has become an area of great interest for both clinicians and researchers because, among other advantages, this would increase the response to new disease-modifying drugs. However, difficulties with compliance and economic costs marginalize many countries worldwide that do not have access to this new type of diagnosis. The opportunity exists to refine the conventional clinical method, without using biomarkers, to attempt an earlier diagnosis as there is information that supports the potential utility of a focused clinical interview, observation of gait and use of more demanding memory tests.

RNA interference of Marlin-1/Jakmip1 results in abnormal morphogenesis and migration of cortical pyramidal neurons.

The formation of the nervous systems requires processes that coordinate proliferation, differentiation and migration of neuronal cells, which extend axons, generate dendritic branching and establish synaptic connections during development. The structural organization and dynamic remodeling of the cytoskeleton and its association to the secretory pathway are critical determinants of cell morphogenesis and migration. Marlin-1 (Jakmip1) is a microtubule-associated protein predominantly expressed in neurons and lymphoid cells. Marlin-1 participates in polarized secretion in lymphocytes, but its functional association with the neuronal cytoskeleton and its contribution to brain development have not been explored. Combining in vitro and in vivo approaches we show that Marlin-1 contributes to the establishment of neuronal morphology. Marlin-1 associates to the cytoskeleton in neurites, is required for the maintenance of an intact Golgi apparatus and its depletion produces the down-regulation of kinesin-1, a plus-end directed molecular motor with a central function in morphogenesis and migration. RNA interference of Marlin-1 in vivo results in abnormal migration of newborn pyramidal neurons during the formation of the cortex. Our results support the involvement of Marlin-1 in the acquisition of the complex architecture and migration of pyramidal neurons, two fundamental processes for the laminar layering of the cortex.

The Republic of Chile: an upper middle-income country at the crossroads of economic development and aging.

Chile is a developing country with a rapidly expanding economy and concomitant social and cultural changes. It is expected to become a developed country within 10 years. Chile is also characterized as being in an advanced demographic transition. Unique challenges are posed by the intersection of rapid economic development and an aging population, making Chile an intriguing case study for examining the impact of these societal-level trends on the aging experience. This paper highlights essential characteristics of this country for understanding its emerging aging society. It reveals that there is a fundamental lack of adequate and depthful epidemiologic and country-specific research from which to fully understand the aging experience and guide new policies in support of health and well-being.

CoREST/LSD1 control the development of pyramidal cortical neurons.

The development of a neuron from a precursor cell comprises a complex set of steps ranging from regulation of the proliferative cycle through the acquisition of distinct morphology and functionality. How these processes are orchestrated is largely unknown. Using in utero manipulation of gene expression in the mouse embryonic cerebral cortex, we found that the transition between multipolar and bipolar stages of newborn cortical pyramidal neurons is markedly delayed by depletion of CoREST, a corepressor component of chromatin remodeling complexes. This profoundly affects the onset of their radial migration. The loss of CoREST function also perturbs the dynamics of neuronal precursor cell populations, transiently increasing the fraction of cells remaining in progenitor states, but not the acquisition of the neuronal glutamatergic fate of pyramidal cells. The function of CoREST in these processes appears to be independent of its best-known interactor, the RE-1 silencer of transcription/neural restrictive silencing factor, and requires the histone demethylase LSD1. This reveals the importance of epigenetic control in the execution of neural development programs, specifically in the cerebral cortex.

Cerebrolysin in Alzheimer's disease.

Cerebrolysin is a neuropeptide preparation mimicking the action of endogenous neurotrophic factors. Positive effects of Cerebrolysin on ß-amyloid- and tau-related pathologies, neuroinflammation, neurotrophic factors, oxidative stress, excitotoxicity, neurotransmission, brain metabolism, neuroplasticity, neuronal apoptosis and degeneration, neurogenesis and cognition were demonstrated in experimental conditions. These pleiotropic effects of Cerebrolysin on Alzheimer's disease-related pathogenic events are consistent with a neurotrophic-like mode of action, and seems to involve the activation of the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 ß intracellular signaling pathway. The clinical efficacy of Cerebrolysin in Alzheimer's disease was evaluated in several randomized, double-blind, clinical trials, showing consistent benefits on global clinical function and cognition, improvements in behavior at high doses, and minor effects on daily living activities in patients with mild to moderate Alzheimer's disease, as well as in subgroups of moderate to moderately severe patients. In addition, the clinical benefits of Cerebrolysin were largely maintained for several months after ending treatment, a finding that supports its discontinuous administration. Cerebrolysin was generally well tolerated and did not induce significant adverse events in Alzheimer's patients. Although long-term studies are needed, the data available suggest that Cerebrolysin is effective as monotherapy and constitutes a promising option for combined therapy in Alzheimer's disease.