Major Neurodegenerative Diseases Research Articles

Assessment of swallowing performance in patients with neurodegenerative disease: A hierarchical cluster analysis.

Swallowing is a complex process that alters with age and neurological diseases; swallowing disorders can be a consequence of both of them. As an advanced multivariate statistical method, hierarchical cluster analysis (HCA) was utilized to make the dendrograms, which was used to find the relationship between the variables. The purpose of this study is to ascertain the type of clustering exhibited by the variables using HCA and to evaluate the approach to major neurodegenerative diseases (MND) with swallowing disorders based on the results obtained. Data were collected from a total of 173 patients from various neurological diagnoses, such as dementia, Parkinson's disease, stroke and polyneuropathy, aging between 42 and 104 (mean of age 72.85) by using the Montreal Cognitive Assessment, the Edinburgh Feeding Evaluation Scale (EdFED), the Eating Assessment Tool (EAT-10), and the Modified Mann Swallowing Ability test. From the collected data, dendrograms were formed by using HCA with Ward linkage method. Based on cluster analysis results, clusters demonstrate statistical significance. They center around EdFED, EAT-10, and age in each MND. In healthy individuals, variables are not clustered as in the patient group. This study holds importance as it can give clinicians a different perspective on determining and managing the elderly population's swallowing problems. The HCA method explicitly proposes which variables should be examined concurrently in the clinic for MND. This research is one of the pioneering studies conducted by using the HCA method.

Serum Beta-Secretase 1 Activity Is a Potential Marker for the Differential Diagnosis between Alzheimer's Disease and Frontotemporal Dementia: A Pilot Study.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two major neurodegenerative diseases causing dementia. Due to similar clinical phenotypes, differential diagnosis is challenging without specific biomarkers. Beta-site Amyloid Precursor Protein cleaving enzyme 1 (BACE1) is a β-secretase pivotal in AD pathogenesis. In AD and mild cognitive impairment subjects, BACE1 activity is increased in brain/cerebrospinal fluid, and plasma levels appear to reflect those in the brain. In this study, we aim to evaluate serum BACE1 activity in FTD, since, to date, there is no evidence about its role. The serum of 30 FTD patients and 30 controls was analyzed to evaluate (i) BACE1 activity, using a fluorescent assay, and (ii) Glial Fibrillary Acid Protein (GFAP) and Neurofilament Light chain (NfL) levels, using a Simoa kit. As expected, a significant increase in GFAP and NfL levels was observed in FTD patients compared to controls. Serum BACE1 activity was not altered in FTD patients. A significant increase in serum BACE1 activity was shown in AD vs. FTD and controls. Our results support the hypothesis that serum BACE1 activity is a potential biomarker for the differential diagnosis between AD and FTD.

Integrative analysis of causal associations between neurodegenerative diseases and colorectal cancer

BackgroundObservational studies have shown that the correlation between neurodegenerative diseases and colorectal cancer (CRC) remains controversial. Therefore, this study aimed to verify the causal association between these two diseases. MethodsMendelian randomization (MR) analysis was used to assess the causal relationships between five major neurodegenerative diseases and CRC. Multivariable MR (MVMR) analysis was conducted to assess the direct causal effect of neurodegenerative diseases on CRC. Colocalization and pathway enrichment analyses were conducted to further elucidate our results. Sensitivity analysis was conducted to assess the robustness of the results. ResultsGenetically predicted Alzheimer's disease (AD) nominally increased CRC risk (OR = 1.0620, 95%CI = 1.0127–1.1136, P = 0.013). There was no causal effect of genetically predicted CRC on neurodegenerative diseases. Furthermore, we demonstrated that genetically predicted AD marginally increased colon cancer risk (OR = 1.1621, 95%CI = 1.0267–1.3153, P = 0.017). Genetically predicted Lewy body dementia (LBD) had a significant causal effect on the increasing risk of colon cancer (IVW OR = 1.1779, 95%CI = 1.0694–1.2975, P = 0.001). MVMR indicated that effect of AD on colon cancer was driven by LBD, type 2 diabetes, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, total cholesterol (TC), processed meat consumption, smoking, alcohol consumption, and educational attainment, whereas the effect of LBD on colon cancer was only influenced by TC. Colocalization and pathway enrichment analysis suggested that LBD and colon cancer possibly shared causal variants (nearby gene APOE), and ERBB4 signaling and lipid metabolism may mediate the causal association between LBD and colon cancer. Sensitivity analysis confirmed the reliability of our findings. ConclusionsOur study demonstrated that genetic vulnerabilities to AD nominally increased the overall risk of CRC and colon cancer. Genetically predicted LBD indicated an elevated risk of colon cancer, potentially linked to ERBB4 signaling and lipid metabolism.

A Machine Learning Approach to Evaluating the Impact of Natural Oils on Alzheimer’s Disease Progression

Alzheimer’s Disease is among the major chronic neurodegenerative diseases that affects more than 50 million people worldwide. This disease irreversibly destroys memory, cognition, and the overall daily activities which occur mainly among the elderly. Few drugs are approved for Alzheimer’s Disease management despite its high prevalence. To date, the available drugs in the market cannot reverse the damage of neurons caused by the disease leading to the exacerbation of symptoms and possibly death. Medicinal plants are considered a rich source of chemical constituents and have been contributing to modern drug discovery in many therapeutic areas including cancer, infectious, cardiovascular, neurodegenerative and Central Nervous System (CNS) diseases. Moreover, essential oils that are extracted from plant organs have been reported for a wide array of biological activities, and their roles as antioxidants, antiaging, cytotoxic, anti-inflammatory, antimicrobial, and enzyme inhibitory activities. This article highlights the promising potential of plants’ essential oils in the discovery of novel therapeutic options for Alzheimer’s Disease and halting its progression. In this article, 428 compounds were reported from the essential oils isolated from 21 plants. A comparative study is carried out by employing a variety of machine learning techniques, validation, and evaluation metrics, to predict essential oils’ efficacy against Alzheimer’s Disease progression. Extensive experiments on essential oil data suggest that a prediction accuracy of up to 82% can be achieved given the proper data preprocessing, feature selection, and model configuration steps. This study underscores the potential of integrating machine learning with natural product research to prioritize and expedite the identification of bioactive essential oils that could lead to effective therapeutic interventions for Alzheimer’s Disease. Further exploration and optimization of machine learning techniques could provide a robust platform for drug discovery and development, facilitating faster and more efficient screening of potential treatments.

Trial Participation in Neurodegenerative Diseases: Barriers and Facilitators: A Systematic Review and Meta-Analysis.

Clinical trials in neurodegenerative diseases often encounter selective enrollment and under-representation of certain patient populations. This delays drug development and substantially limits the generalizability of clinical trial results. To inform recruitment and retention strategies, and to better understand the generalizability of clinical trial populations, we investigated which factors drive participation. We reviewed the literature systematically to identify barriers to and facilitators of trial participation in 4 major neurodegenerative disease areas: Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease. Inclusion criteria included original research articles published in a peer-reviewed journal and evaluating barriers to and/or facilitators of participation in a clinical trial with a drug therapy (either symptomatic or disease-modifying). The Critical Appraisal Skills Program checklist for qualitative studies was used to assess and ensure the quality of the studies. Qualitative thematic analyses were employed to identify key enablers of trial participation. Subsequently, we pooled quantitative data of each enabler using meta-analytical models. Overall, we identified 36 studies, enrolling a cumulative sample size of 5,269 patients, caregivers, and health care professionals. In total, the thematic analysis resulted in 31 unique enablers of trial participation; the key factors were patient-related (own health benefit and altruism), study-related (treatment and study burden), and health care professional-related (information availability and patient-physician relationship). When meta-analyzed across studies, responders reported that the reason to participate was mainly driven by (1) the relationship with clinical staff (70% of the respondents; 95% CI 53%-83%), (2) the availability of study information (67%, 95% CI 38%-87%), and (3) the use or absence of a placebo or sham-control arm (53% 95% CI 32%-72%). There was, however, significant heterogeneity between studies (all p < 0.001). We have provided a comprehensive list of reasons why patients participate in clinical trials for neurodegenerative diseases. These results may help to increase participation rates, better inform patients, and facilitate patient-centric approaches, thereby potentially reducing selection mechanisms and improving generalizability of trial results.

Mutational Landscape of Alzheimer's Disease and Frontotemporal Dementia: Regional Variances in Northern, Central, and Southern Italy.

Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) are the two major neurodegenerative diseases with distinct clinical and neuropathological profiles. The aim of this report is to conduct a population-based investigation in well-characterized APP, PSEN1, PSEN2, MAPT, GRN, and C9orf72 mutation carriers/pedigrees from the north, the center, and the south of Italy. We retrospectively analyzed the data of 467 Italian individuals. We identified 21 different GRN mutations, 20 PSEN1, 11 MAPT, 9 PSEN2, and 4 APP. Moreover, we observed geographical variability in mutation frequencies by looking at each cohort of participants, and we observed a significant difference in age at onset among the genetic groups. Our study provides evidence that age at onset is influenced by the genetic group. Further work in identifying both genetic and environmental factors that modify the phenotypes in all groups is needed. Our study reveals Italian regional differences among the most relevant AD/FTD causative genes and emphasizes how the collaborative studies in rare diseases can provide new insights to expand knowledge on genetic/epigenetic modulators of age at onset.

Human Endogenous Retroviruses in Neurodegenerative Diseases.

Human endogenous retroviruses (HERVs) are DNA transposable elements that have integrated into the human genome via an ancestral germline infection. The potential importance of HERVs is underscored by the fact that they comprise approximately 8% of the human genome. HERVs have been implicated in the pathogenesis of neurodegenerative diseases, a group of CNS diseases characterized by a progressive loss of structure and function of neurons, resulting in cell death and multiple physiological dysfunctions. Much evidence indicates that HERVs are initiators or drivers of neurodegenerative processes in multiple sclerosis and amyotrophic lateral sclerosis, and clinical trials have been designed to target HERVs. In recent years, the role of HERVs has been explored in other major neurodegenerative diseases, including frontotemporal dementia, Alzheimer's disease and Parkinson's disease, with some interesting discoveries. This review summarizes and evaluates the past and current research on HERVs in neurodegenerative diseases. It discusses the potential role of HERVs in disease manifestation and neurodegeneration. It critically reviews antiretroviral strategies used in the therapeutic intervention of neurodegenerative diseases.

Bidirectional two-sample Mendelian randomization analyses support causal relationships between structural and diffusion imaging-derived phenotypes and the risk of major neurodegenerative diseases

Previous observational investigations suggest that structural and diffusion imaging-derived phenotypes (IDPs) are associated with major neurodegenerative diseases; however, whether these associations are causal remains largely uncertain. Herein we conducted bidirectional two-sample Mendelian randomization analyses to infer the causal relationships between structural and diffusion IDPs and major neurodegenerative diseases using common genetic variants-single nucleotide polymorphism (SNPs) as instrumental variables. Summary statistics of genome-wide association study (GWAS) for structural and diffusion IDPs were obtained from 33,224 individuals in the UK Biobank cohort. Summary statistics of GWAS for seven major neurodegenerative diseases were obtained from the largest GWAS for each disease to date. The forward MR analyses identified significant or suggestively statistical causal effects of genetically predicted three structural IDPs on Alzheimer’s disease (AD), frontotemporal dementia (FTD), and multiple sclerosis. For example, the reduction in the surface area of the left superior temporal gyrus was associated with a higher risk of AD. The reverse MR analyses identified significantly or suggestively statistical causal effects of genetically predicted AD, Lewy body dementia (LBD), and FTD on nine structural and diffusion IDPs. For example, LBD was associated with increased mean diffusivity in the right superior longitudinal fasciculus and AD was associated with decreased gray matter volume in the right ventral striatum. Our findings might contribute to shedding light on the prediction and therapeutic intervention for the major neurodegenerative diseases at the neuroimaging level.

Oxidative stress and neurodegenerative diseases: a bidirectional Mendelian randomization study.

Oxidative stress (OS) has been linked to neurodegenerative diseases in numerous epidemiological studies; however, whether it is a pathogenesis or a downstream factor remains controversial. A two-sample bidirectional Mendelian randomization (MR) analysis was implemented to examine evidence of causality of 15 OS injury markers with 3 major neurodegenerative diseases using available genome-wide association studies statistics. As a main approach, inverse-variance weighted (IVW) analysis was performed. The weighted-median (WM) analysis was used to validate the relationship. In order to investigate the existence of horizontal pleiotropy and correct the IVW estimate, the Radial MR approach was applied. To gauge the consistency and robustness of the findings, several sensitivity and pleiotropy analyses were used. For this analysis, p < 0.05 indicates a nominally causal association; according to the Bonferroni correction test, p < 0.0011 indicates a statistically significant causal association. Via IVW and WM, in directional MR, it was genetically predicted that zinc was nominally causally correlated with the risk of Parkinson's disease but not after Bonferroni correction test; alpha-tocopherol was nominally causally correlated with the risk of Amyotrophic lateral sclerosis (ALS) but not after Bonferroni correction test; furthermore, in reverse MR, it was genetically predicted that Alzheimer's disease was causally correlated with uric acid but not after Bonferroni correction test. These above findings were stable across sensitivity and pleiotropy analyses. Based on the current study, there is no authentic genetic causal association between OS biomarkers and neurodegenerative diseases. The complex relationship is required to be confirmed in future experimental research.

Prodromal Status of Rapid Eye Movement Sleep Behavior Disorder: Clinical Significance and Future Perspectives

Rapid eye movement (REM) sleep behavior disorder (RBD) is a prodromal stage for major neurodegenerative diseases, particularly α-synucleinopathies. Recently, the spectrum of RBD is expanding and its prodromal state has been recognized and categorized into isolated REM sleep without atonia and isolated dream-enacting behavior. Although unclear, prodromal RBD frequently occurs in the aged population, with a significantly high phenoconversion rate to RBD and an increased risk of developing neurodegenerative disorders. More active and structured general surveillance of this condition may contribute to the effective modulation of major neurodegenerative diseases. However, the clinical and polysomnographic profiles of prodromal RBD, methods for effective screening and diagnosis of prodromal RBD, and biomarkers for disease progression and phenoconversion must be investigated.

Unlocking the potential of circulating small extracellular vesicles in neurodegenerative disease through targeted biomarkers and advancements in biosensing

Neurodegenerative diseases (NDDs) gradually affect neurons impacting both their function and structure, and they afflict millions worldwide. Detecting these conditions before symptoms arise is crucial for better prognosis and duality of life, given that the disease processes often begin years earlier. Yet, reliable and affordable methods to diagnose NDDs in these stages are currently lacking. There’s a growing interest in using circulating extracellular vesicles (EVs), like small EVs (sEVs) also known as exosomes, as potential sources of markers for screening, diagnosing, and monitoring NDDs. This interest stems from evidence showing that these EVs can carry brain pathological proteins implicated in NDD pathology, and they can even traverse the blood-brain barrier. This review focuses on the creation of EVs, particularly sEVs with a size of less than 200 nanometers, methods for isolating sEVs, and recent advancements in biosensor development to detect NDD-related markers found in sEVs. Furthermore, it explores the potential of sEVs in diagnosing four major NDDs: Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and multiple system atrophy (MSA).

Mitochondrial Permeability Transition, Cell Death and Neurodegeneration.

Neurodegenerative diseases are chronic conditions occurring when neurons die in specific brain regions that lead to loss of movement or cognitive functions. Despite the progress in understanding the mechanisms of this pathology, currently no cure exists to treat these types of diseases: for some of them the only help is alleviating the associated symptoms. Mitochondrial dysfunction has been shown to be involved in the pathogenesis of most the neurodegenerative disorders. The fast and transient permeability of mitochondria (the mitochondrial permeability transition, mPT) has been shown to be an initial step in the mechanism of apoptotic and necrotic cell death, which acts as a regulator of tissue regeneration for postmitotic neurons as it leads to the irreparable loss of cells and cell function. In this study, we review the role of the mitochondrial permeability transition in neuronal death in major neurodegenerative diseases, covering the inductors of mPTP opening in neurons, including the major ones-free radicals and calcium-and we discuss perspectives and difficulties in the development of a neuroprotective strategy based on the inhibition of mPTP in neurodegenerative disorders.

Delineating mechanisms underlying parvalbumin neuron impairment in different neurological and neurodegenerative disorders: the emerging role of mitochondrial dysfunction.

Given the current paucity of effective treatments in many neurological disorders, delineating pathophysiological mechanisms among the major psychiatric and neurodegenerative diseases may fuel the development of novel, potent treatments that target shared pathways. Recent evidence suggests that various pathological processes, including bioenergetic failure in mitochondria, can perturb the function of fast-spiking, parvalbumin-positive neurons (PV+). These inhibitory neurons critically influence local circuit regulation, the generation of neuronal network oscillations and complex brain functioning. Here, we survey PV+ cell vulnerability in the major neuropsychiatric, and neurodegenerative diseases and review associated cellular and molecular pathophysiological alterations purported to underlie disease aetiology.

Revisiting the relevance of Hirano bodies in neurodegenerative diseases.

Hirano bodies (HBs) are eosinophilic pathological structures with two morphological phenotypes commonly found in the hippocampal CA1 region in Alzheimer's disease (AD). This study evaluated the prevalence and distribution of HBs in AD and other neurodegenerative diseases. This cross-sectional study systematically evaluated HBs in a cohort of 193 cases with major neurodegenerative diseases, including AD (n = 91), Lewy body disease (LBD, n = 87), progressive supranuclear palsy (PSP, n = 36), multiple system atrophy (MSA, n = 14) and controls (n = 26). The prevalence, number and morphology of HBs in the stratum lacunosum (HBL) and CA1 pyramidal cell layer were examined. In addition, we investigated the presence of HBs in five additional hippocampal subregions. The morphological types of HBs in CA1 were divided into three, including a newly discovered type, and were evaluated separately, with their morphology confirmed in three dimensions: (1) classic rod-shaped HB (CHB), (2) balloon-shaped HB (BHB) and the newly described (3) string-shaped HB (SHB). The prevalence of each HB type differed between disease groups: Compared with controls, for CHB in AD, AD + LBD, PSP and corticobasal degeneration, for BHB in AD + LBD and PSP, and SHB in AD + LBD and PSP were significantly increased. Regression analysis showed that CHBs were independently associated with higher Braak NFT stage, BHBs with LBD and TDP-43 pathology, SHBs with higher Braak NFT stage, PSP and argyrophilic grain disease and HBLs with MSA. This study demonstrates that HBs are associated with diverse neurodegenerative diseases and shows that morphological types appear distinctively in various conditions.

Principal Component Analysis Enhanced with Bootstrapped Confidence Interval for the Classification of Parkinsonian Patients Using Gaussian Mixture Model and Gait Initiation Parameters.

Parkinson's disease is one of the major neurodegenerative diseases that affects the postural stability of patients, especially during gait initiation. There is actually an increasing demand for the development of new non-pharmacological tools that can easily classify healthy/affected patients as well as the degree of evolution of the disease. The experimental characterization of gait initiation (GI) is usually done through the simultaneous acquisition of about 20 variables, resulting in very large datasets. Dimension reduction tools are therefore suitable, considering the complexity of the physiological processes involved. The principal Component Analysis (PCA) is very powerful at reducing the dimensionality of large datasets and emphasizing correlations between variables. In this paper, the Principal Component Analysis (PCA) was enhanced with bootstrapping and applied to the study of the GI to identify the 3 majors sets of variables influencing the postural control disability of Parkinsonian patients during GI. We show that the combination of these methods can lead to a significant improvement in the unsupervised classification of healthy/affected patients using a Gaussian mixture model, since it leads to a reduced confidence interval on the estimated parameters. The benefits of this method for the identification and study of the efficiency of potential treatments is not addressed in this paper but could be addressed in future works.

Clinical advances in analytical profiling of signature lipids: implications for severe non-communicable and neurodegenerative diseases.

Lipids play key roles in numerous biological processes, including energy storage, cell membrane structure, signaling, immune responses, and homeostasis, making lipidomics a vital branch of metabolomics that analyzes and characterizes a wide range of lipid classes. Addressing the complex etiology, age-related risk, progression, inflammation, and research overlap in conditions like Alzheimer'sDisease, Parkinson's Disease, Cardiovascular Diseases, and Cancer poses significant challenges in the quest for effective therapeutic targets, improved diagnostic markers, and advanced treatments. Mass spectrometry is an indispensable tool in clinical lipidomics, delivering quantitative and structural lipid data, and its integration with technologies like Liquid Chromatography (LC), Magnetic Resonance Imaging (MRI), and few emerging Matrix-Assisted Laser Desorption Ionization- Imaging Mass Spectrometry (MALDI-IMS) along with its incorporation into Tissue Microarray (TMA) represents current advances. These innovations enhance lipidomics assessment, bolster accuracy, and offer insights into lipid subcellular localization, dynamics, and functional roles in disease contexts. The review article summarizes recent advancements in lipidomic methodologies from 2019 to 2023 for diagnosing major neurodegenerative diseases, Alzheimer's and Parkinson's, serious non-communicable cardiovascular diseases and cancer, emphasizing the role of lipid level variations, and highlighting the potential of lipidomics data integration with genomics and proteomics to improve disease understanding and innovative prognostic, diagnostic and therapeutic strategies. Clinical lipidomic studies are a promising approach to track and analyze lipid profiles, revealing their crucial roles in various diseases. This lipid-focused research provides insights into disease mechanisms, biomarker identification, and potential therapeutic targets, advancing our understanding and management of conditions such as Alzheimer'sDisease, Parkinson'sDisease, Cardiovascular Diseases, and specific cancers.

Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca2+ and synaptic defects

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are clinically linked major neurodegenerative diseases. Notably, TAR DNA-binding protein-43 (TDP43) accumulations are hallmark pathologies of FTD/ALS and mutations in the gene encoding TDP43 cause familial FTD/ALS. There are no cures for FTD/ALS. FTD/ALS display damage to a broad range of physiological functions, many of which are regulated by signaling between the endoplasmic reticulum (ER) and mitochondria. This signaling is mediated by the VAPB-PTPIP51 tethering proteins that serve to recruit regions of ER to the mitochondrial surface so as to facilitate inter-organelle communications. Several studies have now shown that disrupted ER-mitochondria signaling including breaking of the VAPB-PTPIP51 tethers are features of FTD/ALS and that for TDP43 and other familial genetic FTD/ALS insults, this involves activation of glycogen kinase-3β (GSK3β). Such findings have prompted suggestions that correcting damage to ER-mitochondria signaling and the VAPB-PTPIP51 interaction may be broadly therapeutic. Here we provide evidence to support this notion. We show that overexpression of VAPB or PTPIP51 to enhance ER-mitochondria signaling corrects mutant TDP43 induced damage to inositol 1,4,5-trisphosphate (IP3) receptor delivery of Ca2+ to mitochondria which is a primary function of the VAPB-PTPIP51 tethers, and to synaptic function. Moreover, we show that ursodeoxycholic acid (UDCA), an FDA approved drug linked to FTD/ALS and other neurodegenerative diseases therapy and whose precise therapeutic target is unclear, corrects TDP43 linked damage to the VAPB-PTPIP51 interaction. We also show that this effect involves inhibition of TDP43 mediated activation of GSK3β. Thus, correcting damage to the VAPB-PTPIP51 tethers may have therapeutic value for FTD/ALS and other age-related neurodegenerative diseases.

Evidence for alterations in lipid profiles and biophysical properties of lipid rafts from spinal cord in sporadic amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is an age-dependent neurodegenerative disease affecting motor neurons in the spinal cord and brainstem whose etiopathogenesis remains unclear. Recent studies have linked major neurodegenerative diseases with altered function of multimolecular lipid-protein complexes named lipid rafts. In the present study, we have isolated lipid rafts from the anterior horn of the spinal cords of controls and ALS individuals and analysed their lipid composition. We found that ALS affects levels of different fatty acids, lipid classes and related ratios and indexes. The most significant changes affected the contents of n-9/n-7 monounsaturated fatty acids and arachidonic acid, the main n-6 long-chain polyunsaturated fatty acid (LCPUFA), which were higher in ALS lipid rafts. Paralleling these findings, ALS lipid rafts lower saturates-to-unsaturates ratio compared to controls. Further, levels of cholesteryl ester (SE) and anionic-to-zwitterionic phospholipids ratio were augmented in ALS lipid rafts, while sulfatide contents were reduced. Further, regression analyses revealed augmented SE esterification to (mono)unsaturated fatty acids in ALS, but to saturates in controls. Overall, these changes indicate that lipid rafts from ALS spinal cord undergo destabilization of the lipid structure, which might impact their biophysical properties, likely leading to more fluid membranes. Indeed, estimations of membrane microviscosity confirmed less viscous membranes in ALS, as well as more mobile yet smaller lipid rafts compared to surrounding membranes. Overall, these results demonstrate that the changes in ALS lipid rafts are unrelated to oxidative stress, but to anomalies in lipid metabolism and/or lipid raft membrane biogenesis in motor neurons.Key messagesThe lipid matrix of multimolecular membrane complexes named lipid rafts are altered in human spinal cord in sporadic amyotrophic lateral sclerosis (ALS).Lipid rafts from ALS spinal cord contain higher levels of n-6 LCPUFA (but not n-3 LCPUFA), n-7/n-9 monounsaturates and lower saturates-to-unsaturates ratio.ALS lipid rafts display increased contents of cholesteryl esters, anomalous anionic-to-zwitterionic phospholipids and phospholipid remodelling and reduced sulphated and total sphingolipid levels, compared to control lipid rafts.Destabilization of the lipid structure of lipid raft affects their biophysical properties and leads to more fluid, less viscous membrane microdomains.The changes in ALS lipid rafts are unlikely related to increased oxidative stress, but to anomalies in lipid metabolism and/or raft membrane biogenesis in motor neurons.

A Review of Deep Learning Approaches for Early Diagnosis of Alzheimer's Disease

Alzheimer's disease (AD), one of the major neurodegenerative diseases, has become the most common cause of dementia problems. Up to now, there is a lack of effective targeted therapeutic drugs and effective treatment modalities to stop the progression of the disease. With the continuous development of computer technology, the use of computer-aided diagnostic technology tools for AD early classification studies will provide clinicians with important assistance. Deep learning-based Alzheimer's disease (AD) imaging classification has become a current research hotspot. In this paper, we first describe the commonly used publicly available datasets in the AD imaging classification task; then introduce the commonly used deep learning classification models for AD diagnosis; secondly, we compare the studies that target different biomarkers of the subjects and the use of unimodal or a combination of different modalities for the early classification of AD; and finally, The challenges of AD classification are summarized and future research directions are proposed.

Establishment of a novel amyotrophic lateral sclerosis patient (TARDBP N345K/+)-derived brain microvascular endothelial cell model reveals defective Wnt/β-catenin signaling: investigating diffusion barrier dysfunction and immune cell interaction.

Amyotrophic lateral sclerosis (ALS) is a major neurodegenerative disease for which there is currently no curative treatment. The blood-brain barrier (BBB), multiple physiological functions formed by mainly specialized brain microvascular endothelial cells (BMECs), serves as a gatekeeper to protect the central nervous system (CNS) from harmful molecules in the blood and aberrant immune cell infiltration. The accumulation of evidence indicating that alterations in the peripheral milieu can contribute to neurodegeneration within the CNS suggests that the BBB may be a previously overlooked factor in the pathogenesis of ALS. Animal models suggest BBB breakdown may precede neurodegeneration and link BBB alteration to the disease progression or even onset. However, the lack of a useful patient-derived model hampers understanding the pathomechanisms of BBB dysfunction and the development of BBB-targeted therapies. In this study, we differentiated BMEC-like cells from human induced pluripotent stem cells (hiPSCs) derived from ALS patients to investigate BMEC functions in ALS patients. TARDBP N345K/+ carrying patient-derived BMEC-like cells exhibited increased permeability to small molecules due to loss of tight junction in the absence of neurodegeneration or neuroinflammation, highlighting that BMEC abnormalities in ALS are not merely secondary consequences of disease progression. Furthermore, they exhibited increased expression of cell surface adhesion molecules like ICAM-1 and VCAM-1, leading to enhanced immune cell adhesion. BMEC-like cells derived from hiPSCs with other types of TARDBP gene mutations (TARDBP K263E/K263E and TARDBP G295S/G295S) introduced by genome editing technology did not show such BMEC dysfunction compared to the isogenic control. Interestingly, transactive response DNA-binding protein 43 (TDP-43) was mislocalized to cytoplasm in TARDBP N345K/+ carrying model. Wnt/β-catenin signaling was downregulated in the ALS patient (TARDBP N345K/+)-derived BMEC-like cells and its activation rescued the leaky barrier phenotype and settled down VCAM-1 expressions. These results indicate that TARDBP N345K/+ carrying model recapitulated BMEC abnormalities reported in brain samples of ALS patients. This novel patient-derived BMEC-like cell is useful for the further analysis of the involvement of vascular barrier dysfunctions in the pathogenesis of ALS and for promoting therapeutic drug discovery targeting BMEC.