Notch Signalling in the Hippocampus of Patients With Motor Neuron Disease

IntroductionThe Notch signalling pathway regulates neuronal survival. It has some similarities with the APP signalling pathway, and competes with the latter for α- and γ-secretase proteolytic complexes. The objective of this study was to study the Notch signalling pathway in the hippocampi of patients with motor neuron disease.MethodsWe studied biological material from the autopsies of 12 patients with motor neuron disease and 4 controls. We analysed the molecular markers of the Notch and APP signalling pathways, TDP43, tau, and markers of neurogenesis.Results and ConclusionLow NICD expression suggests Notch signalling pathway inactivation in neurons. Inactivation of the pathway despite increased Notch1 expression is associated with a lack of α-secretase expression. We observed increased β-secretase expression associated with activation of the amyloid cascade of APP, leading to increases in amyloid-β and AICD peptides and decreased levels of Fe65. Inactivation of the Notch signalling pathway is an important factor in decreased neurogenic response in the hippocampi of patients with amyotrophic lateral sclerosis

FDG-PET-based neural correlates of Addenbrooke’s cognitive examination III scores in Alzheimer’s disease and frontotemporal degeneration

IntroductionThe Addenbrooke’s Cognitive Examination III (ACE-III) is a brief test useful for neuropsychological assessment. Several studies have validated the test for the diagnosis of Alzheimer’s disease (AD) and frontotemporal dementia (FTD). In this study, we aimed to examine the metabolic correlates associated with the performance of ACE-III in AD and behavioral variant FTD.MethodsWe enrolled 300 participants in a cross-sectional study, including 180 patients with AD, 60 with behavioral FTD (bvFTD), and 60 controls. An 18F-Fluorodeoxyglucose positron emission tomography study was performed in all cases. Correlation between the ACE-III and its domains (attention, memory, fluency, language, and visuospatial) with the brain metabolism was estimated.ResultsThe ACE-III showed distinct neural correlates in bvFTD and AD, effectively capturing the most relevant regions involved in these disorders. Neural correlates differed for each domain, especially in the case of bvFTD. Lower ACE-III scores were associated with more advanced stages in both disorders. The ACE-III exhibited high discrimination between bvFTD vs. HC, and between AD vs. HC. Additionally, it was sensitive to detect hypometabolism in brain regions associated with bvFTD and AD.ConclusionOur study contributes to the knowledge of the brain regions associated with ACE-III, thereby facilitating its interpretation, and highlighting its suitability for screening and monitoring. This study provides further validation of ACE-III in the context of AD and FTD

Sera from Patients with NMOSD Reduce the Differentiation Capacity of Precursor Cells in the Central Nervous System

Introduction: AQP4 (aquaporin-4)–immunoglobulin G (IgG)-mediated neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that affects the central nervous system, particularly the spinal cord and optic nerve; remyelination capacity in neuromyelitis optica is yet to be determined, as is the role of AQP4–IgG in cell differentiation. Material and Methods: We included three groups—a group of patients with AQP4–IgG-positive neuromyelitis optica, a healthy group, and a sham group. We analyzed differentiation capacity in cultures of neurospheres from the subventricular zone of mice by adding serum at two different times: early and advanced stages of differentiation. We also analyzed differentiation into different cell lines. Results and Conclusions: The effect of sera from patients with NMOSD on precursor cells differs according to the degree of differentiation, and probably affects oligodendrocyte progenitor cells from NG2 cells to a lesser extent than cells from the subventricular zone; however, the resulting oligodendrocytes may be compromised in terms of maturation and possibly limited in their ability to generate myelin. Furthermore, these cells decrease in number with age. It is very unlikely that the use of drugs favoring the migration and differentiation of oligodendrocyte progenitor cells in multiple sclerosis would be effective in the context of neuromyelitis optica, but cell therapy with oligodendrocyte progenitor cells seems to be a potential alternative

The Integration of Cell Therapy and Biomaterials as Treatment Strategies for Remyelination

Multiple sclerosis (MS) is a chronic degenerative autoimmune disease of the central nervous system that causes inflammation, demyelinating lesions, and axonal damage and is associated with a high rate of early-onset disability. Disease-modifying therapies are used to mitigate the inflammatory process in MS but do not promote regeneration or remyelination; cell therapy may play an important role in these processes, modulating inflammation and promoting the repopulation of oligodendrocytes, which are responsible for myelin repair. The development of genetic engineering has led to the emergence of stable, biocompatible biomaterials that may promote a favorable environment for exogenous cells. This review summarizes the available evidence about the effects of transplantation of different types of stem cells reported in studies with several animal models of MS and clinical trials in human patients. We also address the advantages of combining cell therapy with biomaterials

Inteligencia artificial en deterioro cognitivo y demencias

La inteligencia artificial incluye una serie de técnicas de aplicación e interés creciente en medicina. El campo de la neurología cognitiva y las demencias se enfrenta a múltiples retos, incluyendo la necesidad de realizar un diagnóstico más precoz y certero, y de encontrar tratamientos eficaces. Se revisan las principales aplicaciones de la inteligencia artificial en el campo de las demencias y el deterioro cognitivo, especialmente en la optimización y la automatización de la evaluación cognitiva y de las pruebas de neuroimagen. Se destacan algunas aplicaciones y beneficios para mantener la funcionalidad de los pacientes mediante dispositivos IoT (Internet of Things), así como la implementación de la inteligencia artificial en la generación de nuevos tratamientos y su validación mediante simulaciones, análisis in silico y cerebros virtuales. Las técnicas de inteligencia artificial representan una metodología relevante con múltiples aplicaciones en el campo de la neurología cognitiva. Su implementación probablemente contribuirá de forma decisiva en la mejora diagnóstica, la búsqueda de tratamientos y el avance hacia una medicina de precisión

Underpinnings of verbal fluency in Multiple Sclerosis

Publicado en la sección CorrespondenceThe cognitive and language processes underlying verbal fluency remain unclear. While some cognitive processes related to memory and executive functioning have been more associated with category and letter verbal fluency, other less studied aspects of language ability could be also related. We discuss the contribution of the recent study by Lebkuecher and colleagues (2021) about the role of language in verbal fluency, and the data from other studies evaluating the cognitive and neuroimaging correlates of verbal fluency in MSInstituto de Salud Carlos IIIEuropean CommissionDepto. de Psicobiología y Metodología en Ciencias del ComportamientoFac. de PsicologíaTRUEpu

GA-MADRID: design and validation of a machine learning tool for the diagnosis of Alzheimer’s disease and frontotemporal dementia using genetic algorithms

Artifcial Intelligence aids early diagnosis and development of new treatments, which is key to slow down the progress of the diseases, which to date have no cure. The patients’ evaluation is carried out through diagnostic techniques such as clinical assessments neuroimaging techniques, which provide high-dimensionality data. In this work, a computational tool is presented that deals with the data provided by the clinical diagnostic techniques. This is a Python-based framework implemented with a modular design and fully extendable. It integrates (i) data processing and management of missing values and outliers; (ii) implementation of an evolutionary feature engineering approach, developed as a Python package, called PyWinEA using Mono-objective and Multi-objetive Genetic Algorithms (NSGAII); (iii) a module for designing predictive models based on a wide range of machine learning algorithms; (iv) a multiclass decision stage based on evolutionary grammars and Bayesian networks. Developed under the eXplainable Artifcial Intelligence and open science perspective, this framework provides promising advances and opens the door to the understanding of neurodegenerative diseases from a data-centric point of view. In this work, we have successfully evaluated the potential of the framework for early and automated diagnosis with neuroimages and neurocognitive assessments from patients with Alzheimer’s disease (AD) and frontotemporal dementia (FTD)

Immununochemical Markers of the Amyloid Cascade in the Hippocampus in Motor Neuron Diseases

Background: Several findings suggest that the amyloid precursor protein (APP) and the amyloid cascade may play a role in motor neuron disease (MND).Objective: Considering that dementia is one of the most frequently non-motor symptoms in ALS and that hippocampus is one of the brain areas with greater presence of amyloid related changes in neurodegenerative diseases, our aim was to analyse the molecular markers of the amyloid cascade of APP in pathology studies of the hippocampus of autopsied patients with ALS and ALS-FTD.Methods: We included 9 patients with MND and 4 controls. Immunohistochemical studies and confocal microscopy were used to analyse the expression of APP, TDP-43, pho-TDP-43, Aβ, AICD peptide, Fe65 protein, and pho-TAU in the hippocampus of 7 patients with ALS, 2 patients with ALS-FTD, and 4 controls. These findings were correlated with clinical data.Results: Patients displayed increased expression of APP and Aβ peptide. The latter was correlated with cytoplasmic pho-TDP-43 expression. We also found decreased Fe65 expression. A parallel increase in AICD expression was not found. Patients showed increased expression of pho-TAU in the hippocampus. Findings were similar in patients with ALS and those with ALS-FTD, though more marked in the latter group.Conclusion: Post-mortem analyses showed that the amyloid cascade is activated in the hippocampus of patients with MND and correlated with cytoplasmic pho-TDP-43 expression. The number of intra- or extracellular aggregates of Aβ peptides was not significant