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Neurodegenerative diseases such as Alzheimer´s (AD) and physiological ageing are characterized by a decline in neurogenesis and in the polysialylated isoforms of neural cell adhesion molecule (PSA-NCAM) expression within the hippocampus and specifically in the dentate gyrus (DG). In the 3xTG-AD mouse model, which mimics the human disease in both pathological and behavioral features, this decline in PSA-NCAM is associated with the presence of Aß plaques at 9 months and Tau tangles at 12-15 months. In this work we studied the presence of PSA-NCAM at early ages (1-6 months) in the same model. Our results demonstrated that even as early as the first month of age there is a strong decrease in PSA-NCAM dendritic tree mainly altering the molecular layer (MolL) coverage affecting the synaptic plasticity and furthermore confirmed by the reduction of PSA-NCAM area density (Sv) in the 3xTG-AD. Similar and more marked early changes were seen during aging in both NTG and 3xTg-AD animals. Our results demonstrate for the first time a precipitate decrease of PSA-NCAM cells at such very early phases of the disease. This result suggests an early effect of the disease in the progression of immature and pluripotent cells resulting in an ulterior and early diminution of neurogenesis and therefore an impaired hippocampal cellular and synaptic plasticity.

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There is growing public awareness and concern regarding dementia risk. In addition, genetic testing is increasingly accessible and is at the point of being integrated into routine clinical practice. As a result, there is a pressing need for treating clinicians to have the appropriate knowledge base to request and consent for diagnostic genetic testing in cognitive clinics. We outline our approach to genetic testing in patients with Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies and vascular cognitive impairment. We discuss when to consider testing, the consenting process, and the interpretation and communication of genetic test results.

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BACKGROUND: General practitioners (GPs) play a crucial role in identifying cognitive impairment and dementia and providing post-diagnostic care. This study investigates (1) how promising GP consider lifestyle changes to maintain cognitive performance in general, (2) GP beliefs about the power of modifiable health and lifestyle factors to maintain cognitive performance, and (3) whether those beliefs vary by GP age. METHODS: As part of the AgeWell.de trial, GPs (n = 72) completed a process evaluation questionnaire assessing their perspectives on lifestyle changes to preserve cognitive performance in elderly patients. In greater detail, their perceived efficacy of established risk and protective factors was investigated using a 5-point Likert scale. Descriptive statistical analyses were performed for research question (1) and (2). Spearman´s rank correlations and ordinal logistic regressions were used to answer research question (3). All results were interpreted exploratively. RESULTS: GPs rated the overall chance of lifestyle changes maintaining cognitive performance quite neutral with a median score of 3.0 (IQR = 2.0). They rated the efficacy of all the modifiable health and lifestyle factors high, with increase in physical and social activity ((Mdn = 5.0, IQR = 1.0) receiving the highest ratings with the narrowest range. Spearman's rank correlation indicated a significant positive relationship between age and the belief in "Optimization of nutrition" for preventing cognitive decline and dementia (ρ = .255, p = .041). However, ordinal logistic regressions showed no significant relationships between age and GP ratings of lifestyle change efficacy. CONCLUSION: These findings highlight the positive perception of GPs on the efficacy of modifiable health and lifestyle factors for preventing cognitive decline and dementia. TRIAL REGISTRATION: The AgeWell.de trial is registered in the German Clinical Trials Register (DRKS; trial identifier: DRKS00013555, Registration Date 07 December 2017).

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Synaptic dysfunction is an early feature in Alzheimer's disease (AD) pathogenesis and a major morphological correlate of memory deficits. Given the main synaptic location of N-methyl-D-aspartate receptors (NMDARs), their dysregulation has been implicated in these pathological effects. Here, to detect possible alterations in the expression and synaptic localisation of the GluN1 subunit in the brain of amyloidogenic APP/PS1 mice, we employed histoblot and SDS-digested freeze-fracture replica labelling (SDS-FRL) techniques. Histoblots showed that GluN1 expression was significantly reduced in the hippocampus in a layer-dependent manner, in the cortex and the caudate putamen of APP/PS1 transgenic mice at 12 months of age but was unaltered at 1 and 6 months. Using quantitative SDS-FRL, we unravelled the molecular organisation of GluN1 in seven excitatory synapse populations at a high spatial resolution in the CA1 and CA3 fields and the DG of the hippocampus in 12-month-old APP/PS1 mice. In the CA1 field, the labelling density for GluN1 in the excitatory synapses established on spines and interneurons, was significantly reduced in APP/PS1 mice compared to age-matched wild-type mice in the stratum lacunosum-moleculare but unaltered in the stratum radiatum. In the CA3 field, synaptic GluN1 was reduced in mossy fibre-CA3 pyramidal cell synapses but unaltered in the A/C-CA3 pyramidal cell synapses. In the DG, the density of GluN1 in granule cell-perforant pathway synapses was reduced in APP/PS1 mice. Altogether, our findings provide evidence of specific alterations of synaptic GluN1 in the trisynaptic circuit of the hippocampus in Aß pathology. This differential vulnerability in the disruption of NMDARs may be involved in the mechanisms causing abnormal network activity of the hippocampal circuit and cognitive impairment characteristic of APP/PS1 mice.

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Alzheimer's disease (AD) constitutes a major public-health issue of our time. Regrettably, despite our considerable understanding of the pathophysiological aspects of this disease, current interventions lead to poor outcomes. Furthermore, experimentally promising compounds have continuously failed when translated to clinical trials. Along with increased population ageing, Type 2 Diabetes Mellitus (T2DM) has become an extremely common condition, mainly due to unbalanced dietary habits. Substantial epidemiological evidence correlates T2DM with cognitive impairment as well. Considering that brain insulin resistance, mitochondrial dysfunction, oxidative stress, and amyloidogenesis are common phenomena, further approaching the common features among these pathological conditions. Metformin constitutes the first-choice drug to preclude insulin resistance in T2DM clinical management. Experimental evidence suggests that its functions might include neuroprotective effects, in addition to its hypoglycemic activity. This review aims to summarize and discuss current knowledge of experimental data on metformin on this path towards translational medicine. Finally, we discuss the controversial data of responses to metformin in vitro, and in vivo, animal models and human studies.

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About 80 % of brain disorders have a genetic basis. The pathogenesis of most neurodegenerative diseases is associated with a myriad of genetic defects, epigenetic alterations (DNA methylation, histone/chromatin remodeling, miRNA dysregulation), and environmental factors. The emergence of new sequencing technologies and tools to study the epigenome has led to identifying predictive biomarkers for earlier diagnosis, opening up the possibility of prophylactical interventions. As a result, advances in pharmacogenetics and pharmacoepigenomics now allow for personalized treatments based on the profile of each patient and the specific genetic and epigenetic mechanisms involved. This Review highlights the complexity of neurodegenerative diseases and the variability in patient responses to pharmacotherapy, emphasizing the influence of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of drugs used to treat those conditions. We specifically discuss the potential modulatory effect of several genetic polymorphisms associated with an increased risk of developing different neurodegenerative diseases. We explore genetic and genomic technologies and the potential of analyzing individual-specific drug metabolism to predict and influence drug response and associated clinical outcomes. We also provide insights into the mechanism of action of the drugs under investigation and their potential impact on disease-modifying pathways. Finally, the Review underscores the great potential of this field to enhance the effectiveness and safety of drug treatments through personalized medicine.

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Alterations in cognitive and non-cognitive cerebral functions characterize Alzheimer's disease (AD). Cortical and hippocampal impairments related to extracellular accumulation of Aß in AD animal models have been extensively investigated. However, recent reports have also implicated intracellular Aß in limbic regions, such as the nucleus accumbens (nAc). Accumbal neurons express high levels of inhibitory glycine receptors (GlyRs) that are allosterically modulated by ethanol and have a role in controlling its intake. In the present study, we investigated how GlyRs in the 2xTg mice (AD model) affect nAc functions and ethanol intake behavior. Using transgenic and control aged-matched litter mates, we found that the GlyRα2 subunit was significantly decreased in AD mice (6-month-old). We also examined intracellular calcium dynamics using the fluorescent calcium protein reporter GCaMP in slice photometry. We also found that the calcium signal mediated by GlyRs, but not GABAAR, was also reduced in AD neurons. Additionally, ethanol potentiation was significantly decreased in accumbal neurons in the AD mice. Finally, we performed drinking in the dark (DID) experiments and found that 2xTg mice consumed less ethanol on the last day of DID, in agreement with a lower blood ethanol concentration. 2xTg mice also showed lower sucrose consumption, indicating that overall food reward was altered. In conclusion, the data support the role of GlyRs in nAc neuron excitability and a decreased glycinergic activity in the 2xTg mice that might lead to impairment in reward processing at an early stage of the disease.

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BACKGROUND: Alzheimer's Disease (AD), undergoing a faster increase in occurrence than any other type of dementia, lacks a curative remedy despite advanced discoveries. To explore the realm of non-pharmacologic therapies, our study evaluates the 12-week impact of non-invasive Photobiomodulation (PBM) on cognitive and psychological aspects in individuals with AD and minimal cognitive impairment (MCI). The urgency of exploring innovative interventions is underscored by the rising occurrence of AD, particularly in regions with aging populations like Iran. METHOD: 13 patients (6 case patients and 7 control patients) participated in the study. Sham treatment was administered to seven individuals, while another six received PBM treatment over 12 weeks, with daily at-home LED (810 nm wavelength) device usage lasting 20 min. Initially, the patient and their caregiver participated in two hospital sessions to acquaint them with the device's operation. RESULTS: The mean reduction of Hamilton's anxiety questionnaire score was 3.33±6.08 in the intervention group and 2.00±3.46 in the control group (p-value=0.836). The mean score reduction of the Hamilton depression questionnaire was 3.16±3.86 in the intervention group and 4.85±6.20 in the control group (p-value=0.836). The mean score of the DAD questionnaire in the intervention group before the study was 25.50±13.13 and after the intervention was 29.83±12.12 (p-value=0.084) and in the control group it was 29.71±8.19 and after the study was 29±0.972 (p-value = 0.526). The mean changes in the DAD questionnaire score in the intervention group increased by 4.33±4.92 and decreased by 0.71±2.81 in the control group (p-value=0.041). CONCLUSION: In general, PBM appears to hold promise as a potentially safe method for enhancing the cognitive, functional, and psychological status of individuals with Alzheimer's disease, though further research with larger sample size and cautious interpretation are warranted.

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Alzheimer's disease (AD) is the most common form of dementia with no cure so far, probably due to the complexity of this multifactorial disease with diverse processes associated with its origin and progress. Several neuropathological hallmarks have been identified that encourage the search for new multitarget drugs. Therefore, following a multitarget approach, nine rivastigmine-indole (RIV-IND) hybrids (5a1-3, 5b1-3, 5c1-3) were designed, synthesized and evaluated for their multiple biological properties and free radical scavenging activity, as potential multitarget anti-AD drugs. The molecular docking studies of these hybrids on the active center of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) suggest their capacity to act as dual enzyme inhibitors with probable greater disease-modifying impact relative to AChE-selective FDA-approved drugs. Compounds 5a3 (IC50 = 10.9 µM) and 5c3 (IC50 = 26.8 µM) revealed higher AChE inhibition than the parent RIV drug. Radical scavenging assays demonstrated that all the hybrids containing a hydroxyl substituent in the IND moiety (5a2-3, 5b2-3, 5c2-3) have good antioxidant activity (EC50 7.8-20.7 µM). The most effective inhibitors of Aß42 self-aggregation are 5a3, 5b3 and 5c3 (47.8-55.5%), and compounds 5b2 and 5c2 can prevent the toxicity induced by Aß1-42 to cells. The in silico evaluation of the drug-likeness of the hybrids also showed that all the compounds seem to have potential oral availability. Overall, within this class of RIV-IND hybrids, 5a3 and 5c3 appear as lead compounds for anti-AD drug candidates, deserving further investigation.

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Introducción La miastenia gravis (MG) y la enfermedad de Alzheimer (EA) son dos de las enfermedades neurológicas en cuya fisiopatología interviene la acetilcolina en distintos niveles. En la primera, la alteración de este neurotransmisor se produce en la unión neuromuscular, y en la segunda, en el sistema nervioso central. Objetivo Analizar la posible relación entre dichas patologías estudiando la prevalencia y la odds ratio de la EA dentro de los pacientes diagnosticados de MG con respecto a la prevalencia de EA en la población general. Pacientes y métodos Se han examinado datos de las historias clínicas electrónicas del sistema de salud de Castilla-La Mancha utilizando el procesamiento de lenguaje natural a través de la plataforma clínica de inteligencia artificial Savana Manager?. Resultados Se ha identificado a 970.503 pacientes mayores de 60 años, de los que 1.028 tenían diagnóstico de MG. La proporción de pacientes con diagnóstico de EA dentro de este grupo (4,28%) es mayor que en el resto de la población (2,82%; p = 0,0047), con una odds ratio de 1,54 (intervalo de confianza al 95%: 1,13-2,08; p = 0,0051), sin que se encuentren diferencias significativas en el análisis bivariante del resto de los factores de riesgo para EA más importantes conocidos hasta ahora. Conclusiones Nuestros resultados sugieren que podría existir un aumento de la prevalencia de EA en pacientes con MG. (AU)

INTRODUCTION Myasthenia gravis (MG) and Alzheimer’s disease (AD) are two of the most important diseases where the dysregulation of acetylcholine activity plays a crucial role. In the first, this dysregulation happens at the level of the neu­romuscular junction and in the second, in the central nervous system (CNS). AIM To analyze the possible relationship between these two pathologies, analyzing the prevalence and the odds ratio of AD within patients previously diagnosed with MG. We will compare these data with respect to the prevalence of AD in the general population. PATIENTS AND METHODS We examined the data obtained by the electronic medical records of patients in the health care system of Castilla La Mancha using the Natural Language Process provided by a clinical platform of artificial intelligence known as the Savana Manager?. RESULTS We identified 970,503 patients over the age of 60 years, of which 1,028 were diagnosed with MG. The proportion of the patients diagnosed with AD within this group (4.28%) was greater than the rest of the population (2.82%) (p = 0,0047) with an odds ratio of 1.54 (confidence interval at 95% 1.13-2.08; p = 0.0051) without finding significant differences in the bivariate analysis for the rest of the most important actual known risk factors for AD. CONCLUSION. Our results suggest that there might be an increase in the prevalence of AD in patients previously diagnosed with MG. (AU)

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Alzheimer' s disease (AD) is a progressive neurodegenerative disorder histologically characterized by the presence of senile plaques and neurofibrillary tangles (NFTs) found in and around pyramidal neurons in cortical tissue. Mounting evidence suggests regional increased iron load and dyshomeostasis have been associated with oxidative stress, oxidation of proteins and lipids, and cell death, and appears to be a risk factor for more rapid cognitive decline, thereby involved in multiple aspects of the pathophysiology of AD. Ferroptosis is a newly identified iron-dependent lipid peroxidation-driven cell death and emerging evidences have demonstrated the involvement of ferroptosis in the pathological process of AD. Notably, some novel compounds targeting ferroptosis can relieve AD-related pathological symptoms in AD cells and animal model and exhibit potential clinical benefits in AD patients. This review systematically summarizes the growing molecular and clinical evidence implicating ferroptosis in the pathogenesis of AD, and then reviews the application of ferroptosis inhibitors in mouse/cell models to provide valuable information for future treatment and prevention of AD.

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Objective To investigate the relieving effects of knockdown of long non-coding RNA(lncRNA)taurine up-regulated gene 1 (TUG1) on inhibiting nucleotide binding oligomerization domain like receptor protein 1 (NLRP1) inflammasome and the progression of Alzheimer’ s disease. Methods Wild-type (WT group, 10 mice) or amyloid precursor protein (APP) / presenilin-1 (PS1) transgenic mice (30 mice) with a genetic background of C57 / BL6 aged 9-10 weeks were used in this study. APP / PS1 transgenic mice were randomly divided into model group, model+lncRNA TUG1 short hairpin RNA (shRNA) group and model + shRNA non target (NT) group (n = 10) . Blood samples, cerebral cortex tissues, primary microglial cells and primary astrocytes were collected from mice 12 weeks of age on day 1 (3-month-old) and 32 weeks of age on day 1 (8-month-old), with 5 mice per group at each time point. Real-time PCR analysis was used to detect the expression levels of lncRNA TUG1 and macrophage migration inhibitory factor (MIF) mRNA in cerebral cortex tissues and primary microglial cells, and C1r and C1s mRNA levels in primary astrocytes of 3-month-old and 8-month-old mice in the above 4 groups, respectively. ELISA was used to determine the MIF in plasma samples of the above 4 groups of mice. Primary microglia and astrocytes from the cerebral cortex of 3-month-old and 8-month-old mice were co-cultured. CCK-8 method was used to determine the proliferation ability of the above cells. Western blotting was used to determine the expression levels of MIF, pro interleukin-1β (pro-IL-1β), apoptosis associated speck-like protein containing a caspase recrult domain(ASC), Caspase-1 (p20), Caspase-1 (full), NLRP1 and NLRP3 in cerebral cortex tissues of 3-month-old and 8-month-old mice. Immunofluorescent staining was used to determine amyloid beta(Aβ) in cerebral cortex of 8-month-old mice. Results At the age of 3-month-old and 8-month-old, compared with the WT group, the relative expression level of lncRNA TUG1 and MIF in cerebral cortex tissues and primary microglia of model group mice was significantly up-regulated, with primary microglial cells and astrocytes proliferation ability enhanced (P0. 05) . There was no significant difference between the model group and the model+shRNA NT group mice of all the above factors (P>0. 05) . Conclusion In APP / PS1 transgenic mice, up-regulation of lncRNA TUG1 and MIF are positively associated with the activation of NLRP1 inflammasome in mice cerebral cortex tissues and primary microglia. Knock-down of lncRNA TUG1 can ameliorate the progression of Alzheimer’ s disease.

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Dendritic spine features in human neurons follow the up-to-date knowledge presented in the previous chapters of this book. Human dendrites are notable for their heterogeneity in branching patterns and spatial distribution. These data relate to circuits and specialized functions. Spines enhance neuronal connectivity, modulate and integrate synaptic inputs, and provide additional plastic functions to microcircuits and large-scale networks. Spines present a continuum of shapes and sizes, whose number and distribution along the dendritic length are diverse in neurons and different areas. Indeed, human neurons vary from aspiny or "relatively aspiny" cells to neurons covered with a high density of intermingled pleomorphic spines on very long dendrites. In this chapter, we discuss the phylogenetic and ontogenetic development of human spines and describe the heterogeneous features of human spiny neurons along the spinal cord, brainstem, cerebellum, thalamus, basal ganglia, amygdala, hippocampal regions, and neocortical areas. Three-dimensional reconstructions of Golgi-impregnated dendritic spines and data from fluorescence microscopy are reviewed with ultrastructural findings to address the complex possibilities for synaptic processing and integration in humans. Pathological changes are also presented, for example, in Alzheimer's disease and schizophrenia. Basic morphological data can be linked to current techniques, and perspectives in this research field include the characterization of spines in human neurons with specific transcriptome features, molecular classification of cellular diversity, and electrophysiological identification of coexisting subpopulations of cells. These data would enlighten how cellular attributes determine neuron type-specific connectivity and brain wiring for our diverse aptitudes and behavior.

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Metabolic syndrome (MetS), a cluster of metabolic conditions that include obesity, hyperlipidemia, and insulin resistance, increases the risk of several aging-related brain diseases, including Alzheimer's disease (AD). However, the underlying mechanism explaining the link between MetS and brain function is poorly understood. Among the possible mediators are several adipose-derived secreted molecules called adipokines, including adiponectin (ApN) and resistin, which have been shown to regulate brain function by modulating several metabolic processes. To investigate the impact of adipokines on MetS, we employed a diet-induced model to induce the various complications associated with MetS. For this purpose, we administered a high-fat diet (HFD) to both WT and APP/PSN1 mice at a pre-symptomatic disease stage. Our data showed that MetS causes a fast decline in cognitive performance and stimulates Aß42 production in the brain. Interestingly, ApN treatment restored glucose metabolism and improved cognitive functions by 50% while decreasing the Aß42/40 ratio by approximately 65%. In contrast, resistin exacerbated Aß pathology, increased oxidative stress, and strongly reduced glucose metabolism. Together, our data demonstrate that ApN and resistin alterations could further contribute to AD pathology.

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Alzheimer's disease (AD) ranks first among the causes of dementia worldwide. AD can develop a psychotic manifest at a significant rate. AD prognosis worsens by added psychosis clinic. There is no treatment approved by the United States Food and Drug Administration (FDA) among antipsychotics for Alzheimer's disease Psychosis (ADP). However, pimavanserine, an atypical antipsychotic, has been approved by the FDA for Parkinson's psychosis. It is predicted that pimavanserin, a new antipsychotic, will fill an important gap in this area. In clinical trials, it appears to be effective in the treatment of delusions and hallucinations at psychosis in both Parkinson's and AD. In this systematic review, we evaluated the analysis of current literature data on pimavanserin used in ADP. We searched the existing literature on clinical studies on pimavanserin therapy used in ADP. Data were determined by systematically searching PubMed, MEDLINE, EMBASE, and Google Scholar until December 2022. A total of 35 citations were found and uploaded on the Mendeley program. Abstracts and full texts of literature data were examined. Pimavanserin was observed, and satisfactory results were obtained in treating ADP. Pimavanserin has a unique mechanism of action. Pimavanserin, an atypical antipsychotic drug, has a low affinity for 5-HT2C receptors and has selective 5-HT2A reverse agonist/antagonist action. Pimavanserin has no clinically significant affinity for dopaminergic, histaminergic, muscarinic or adrenergic receptors. This agent may also achieve significant positive results in resistant psychosis treatments.

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The spectrum of neurodegenerative diseases that primarily affect cognition and behaviorspreads from asymptomatic preclinical disease to very mild cognitive impairment to frank dementia. Alzheimer's disease (AD) is the most common cause of a decline in cognitive ability. Also, it is a devastating condition that affects patients and their entirefamilies of caregivers, exacting tremendous financial hardships. Diagnosis may be complicated by other forms of dementia that have symptoms and pathologies similar to AD. Knowing the key features and pathology of each type of dementia can help in the accurate diagnosis of patients, so they will receive the treatment and support services appropriate for their condition and maintain the highest possible functioning in daily life and quality of life. Differentiate, based on clinical criteria, neuropathology, and biomarkers, AD and its atypical variants from other common dementias including Dementia with Lewy Bodies, Vascular Cognitive Impairment, Frontotemporal Degeneration, and less frequent cognitive disorders. The importance of getting an accurate and early diagnosis of dementiais now increasingly significant to make important decisions about treatment, support, and care. Nonpharmacological as well as pharmacological interventions should be initiated once the diagnosis is obtained. Biochemical markers to identify Alzheimer's disease play a central role in the new diagnostic criteria for the disease and in the recent biological definition of AD. This review article presents up-to-date data regarding the recent diagnostic criteria of Alzheimer´s disease and related disorders, emphasizing its usefulness in routine clinical practice.

El espectro de enfermedades neurodegenerativas que afectan principalmente a la cognición y el comportamiento abarca desde la enfermedad preclínica asintomática hasta el deterioro cognitivo muy leve y la demencia franca. La enfermedad de Alzheimer (EA) es la causa más común de deterioro de la capacidad cognitiva. Es una enfermedad devastadora que afecta a los pacientes y a toda su familia de cuidadores, lo que supone enormes dificultades socioeconómicas y psicoemocionales. El diagnóstico puede complicarse debido a otras formas de demencia que presentan síntomas y patologías similares a la EA. Los marcadores bioquímicos para identificar la enfermedad de Alzheimer desempeñan un papel central en los nuevos criterios diagnósticos de la enfermedad y en la reciente definición biológica de la EA. Conocer las características claves y la patología de cada tipo de demencia puede ayudar en el diagnóstico preciso de los pacientes, a fin de que reciban el tratamiento y los servicios de apoyo adecuados a su condición y mantengan el mayor funcionamiento posible en la vida diaria y la calidad de vida. Por lo tanto es prioritario diferenciar, basándose en criterios clínicos, neuropatología y biomarcadores, la EA y sus variantes atípicas de otras demencias comunes como el Deterioro Cognitivo Vascular, la Degeneración Fronto- temporal entre otras, y los trastornos cognitivos menos frecuentes. Este artículo de revisión presenta datos actualizados relativos a los recientes criterios diagnósticos de algunas formas de demencia haciendo hincapié en su utilidad en la práctica clínica habitual. Se exponen los criterios de EA, de Demencia Vascular (DV), de la demencia Fronto-temporal (DFT) y de una forma rara de demencia, descripta en los últimos años, que se evidencia en pacientes muy añosos con un perfil similar a la EA. Se trata de la encefalopatía predominantemente límbica por tdp- 43 relacionada a la edad (LATE).

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Structural analysis of the central 12 residue stretch of Amyloid precursor protein Intracellular Domain (AICD16-27: T-S-I-H-H-G-V-V-E-V-D-A) was carried out by NMR and homology modeling. Further, metal and polyphenol interactions were also carried out for these 12 residues stretch, as it contains two critical Histidine residues, which were observed to be perturbed via NMR. A full length 57 residues AICD model was generated via computational methods, to ascertain its overall conformation, as the entire structure was unavailable. An overlay of this AICD entire model with the full length Aß-42 structure matched well, implying similar properties. Docking studies with metals and polyphenols indicated involvement of the key Histidine residues highlighting their roles towards neurodegeneration and AD pathophysiology.Communicated by Ramaswamy H. Sarma.

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Alzheimer's disease (AD) is the most common cause of neurodegenerative cognitive impairment. Brain stimulation techniques based on the delivery of transcranial shockwaves are currently being studied for their increasing popularity as an approach to modulate the human brain in a focal and targeted manner making this therapy a promising line of action against AD. In the present manuscript, we review for further understanding whether transcranial pulse stimulation (TPS) is a beneficial treatment for AD patients. PubMed, Google Scholar, and Cochrane databases were accessed with the search criteria set from year 2001 to 2022 and the following keywords were used: "transcranial pulse stimulation", "focused ultrasound", "noninvasive treatment and Alzheimer" and "TPS". The search was focused on papers that provide evidence on the biological bases of the method, as well as its safety and tolerability. Even though more studies are needed with greater scientific rigor, such as a doubleblind and randomized study versus a placebo, TPS is an excellent and safe therapeutic option for AD. This novel approach accompanies currently available treatments and complements them, helping to maintain greater stability of the disease and slowing its progression. The biological effects and potential mechanisms of action of TPS for the improvement of cognitive function are further discussed.

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Adult hippocampal neurogenesis enhances brain plasticity and contributes to the cognitive reserve during aging. Adult hippocampal neurogenesis is impaired in neurological disorders, yet the molecular mechanisms regulating the maturation and synaptic integration of new neurons have not been fully elucidated. GABA is a master regulator of adult and developmental neurogenesis. Here we engineered a novel retrovirus encoding the fusion protein Gephyrin:GFP to longitudinally study the formation and maturation of inhibitory synapses during adult hippocampal neurogenesis in vivo. Our data reveal the early assembly of inhibitory postsynaptic densities at 1 week of cell age. Glycogen synthase kinase 3 Beta (GSK-3ß) emerges as a key regulator of inhibitory synapse formation and maturation during adult hippocampal neurogenesis. GSK-3ß-overexpressing newborn neurons show an increased number and altered size of Gephyrin+ postsynaptic clusters, enhanced miniature inhibitory postsynaptic currents, shorter and distanced axon initial segments, reduced synaptic output at the CA3 and CA2 hippocampal regions, and impaired pattern separation. Moreover, GSK-3ß overexpression triggers a depletion of Parvalbumin+ interneuron perineuronal nets. These alterations might be relevant in the context of neurological diseases in which the activity of GSK-3ß is dysregulated.

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