REVIEW | doi:10.20944/preprints202107.0116.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Parkinson’s disease; Alzheimer’s Disease; Clinical trial; Precision medicine.
Online: 5 July 2021 (16:08:41 CEST)
Concomitant neuropathological hallmarks of Alzheimer’s Disease (AD) are common in the brains of people with Parkinson’s disease (PD). Furthermore, AD biomarkers are associated with cognitive decline and dementia in PD patients during life. Here, we highlight the considerable overlap between AD and PD, emphasizing neuropathological, biomarker, and mechanistic studies. We suggest that precision medicine approaches may successfully identify PD patients most likely to develop concomitant AD. The ability to identify PD patients at high risk for future concomitant AD in turn provides an ideal cohort for trials of AD-directed therapies in PD patients, aimed at delaying or preventing cognitive symptoms.
REVIEW | doi:10.20944/preprints201909.0270.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s disease; clinical trial fails; disease-modifying treatments; alzheimer’s disease biomarkers; combination treatment; clinical trial designs
Online: 24 September 2019 (11:23:25 CEST)
Despite all scientific efforts and many protracted and expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or have been abandoned in the last decade. The most probable explanations for failures of disease-modifying treatments (DMTs) for AD may include late initiation of treatments during the course of AD development, inappropriate drug dosages, erroneous selection of treatment targets, and mainly an inadequate understanding of the complex pathophysiology of AD, which may necessitate combination treatments rather than monotherapy. Clinical trials’ methodological issues have also been criticized. Current drug-development research for AD is aimed to overcome these drawbacks. Preclinical and prodromal AD populations, as well as traditionally investigated populations representing all the clinical stages of AD, are included in recent trials. Systematic use of biomarkers in staging preclinical and prodromal AD and of a single primary outcome in trials of prodromal AD are regularly integrated. The application of amyloid, tau, and neurodegeneration biomarkers, including new biomarkers—such as Tau positron emission tomography, neurofilament light chain (blood and CSF biomarker of axonal degeneration) and neurogranin (CSF biomarker of synaptic functioning)—to clinical trials allows more precise staging of AD. Additionally, use of the Bayesian statistics, modifiable clinical trial designs, and clinical trial simulators enrich the trial methodology. Besides, combination therapy regimens are currently assessed in clinical trials. The abovementioned diagnostic and statistical advances, which have been recently integrated in clinical trials, are consequential to the recent failures of studies of disease-modifying treatments. Their experiential rather than theoretical origins may better equip potentially successful drug-development strategies.
REVIEW | doi:10.20944/preprints202305.1673.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: Microglia; Neuroinflammation; Alzheimer’s Disease
Online: 24 May 2023 (02:50:56 CEST)
Microglia together with other permanent macrophages in central nervous system (CNS) are responsible for regulating the innate immune response of the brain and spinal cord. Upon activation, microglia triggers the release of inflammatory mediators such as cytokines, chemokines, and other proteins related to neuro-inflammation. Elevated levels of neuro-inflammation have been linked to a decline in cognitive performance manifested in Alzheimer’s Disease (AD). There are mounting evidence in the literature to suggest that microglia are responsible for a substantial amount of the synaptic damage seen in AD. Most importantly, scientific studies have suggested that overexpression of microglia-derived neuro-inflammation elevates amyloid beta (Aβ) plaque formation, and hyperactivation of tau protein; the two main pathological characteristic features of AD. Alternatively, Aβ and tau formation further activate microglia to sustain the neuro-inflammation triggering a vicious cascade of neurodegeneration in AD. Here in this review, we discussed the role of microglia associated neuroinflammation for the pathogenesis of AD.
REVIEW | doi:10.20944/preprints202101.0527.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: lactic acid; ceramide; folate; nicotinamide; Alzheimer’s disease
Online: 26 January 2021 (08:25:13 CET)
Keywords: lactic acid; ceramide; folate; nicotinamide; Alzheimer’s disease
REVIEW | doi:10.20944/preprints201712.0023.v2
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: physical exercise; irisin; neurodegeneration; aging; Alzheimer’s disease
Online: 11 February 2018 (04:28:07 CET)
Irisin, a skeletal muscle-secreted myokine, produced in response to physical exercise, has protective functions in both the central and the peripheral nervous systems, including the regulation of brain-derived neurotrophic factors and modification of telomere length. Such beneficial effects may inhibit or delay the emergence of neurodegenerative diseases, including Alzheimer’s disease (AD). This review is based on the hypothesis that irisin produced by physical exercise helps control AD progression. Herein, we describe the physiology of irisin and its potential role in delaying or preventing AD. Although current and ongoing studies on irisin show promising results, further research is required to clarify its potential as a meaningful therapeutic target for treating human diseases.
ARTICLE | doi:10.20944/preprints202105.0032.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Alzheimer’s disease; cellular prion protein; amyloid β and PrP interaction in Alzheimer’s; BACE1; Aβ
Online: 5 May 2021 (10:45:04 CEST)
Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Pathological deposits of neurotoxin proteins within the brain, such as amyloid-Beta and hyperphosphorylated tau tangles, are prominent features in AD. The prion protein (PrP) is involved in neurodegeneration via its conversion from the normal cellular form PrPc, to the infection form PrP Sc. Some studies indicated that posttranslationally modified PrPc isoforms plays a fundamental role in AD pathological progression. Several studies have shown that interaction of Aβ oligomers with N-terminal residues of the PrPc protein region appears critical for neuronal toxicity. The PrPc-Aβ binding always occur in AD brains and is never detected in nondemented controls and the binding of Aβ aggregates to PrPc is restricted to the N-terminus of PrPc.
REVIEW | doi:10.20944/preprints202002.0203.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: Alzheimer’s disease; biomarkers dynamics; interaction; time order
Online: 15 February 2020 (15:06:18 CET)
The Aβ cascade and alternations of biomarkers in neuro-inflammation, synaptic dysfunction and neuronal injury followed by Aβ have progressed. But the question is how to use the biomarkers. Here, we examine the evidence and pathogenic implications of protein interactions and the time order of alternation. After the deposition of Aβ, the change of tau, NfL and NG is the main alternation and connection to others. The neuro-inflammation, synaptic dysfunction and neuronal injury function is exhibited prior the structural and metabolic changes in the brain following Aβ deposition. The time order of such biomarkers compared to the tau protein is not clear. Despite the close relationship between biomarkers and plaque Aβ deposition, several factors favor one or the other. There is an interaction between the proteins that CSF SNAP-25, VILIP-1 and YKL-40 can predict the brain amyloid burden. The Aβ cascade hypothesis could be the pathway, but not all subjects are converted to AD, even with very high elevated Aβ. The interaction of biomarkers and the time order of change require further research to identify the right subjects and right molecular target for precision medicine therapies.
ARTICLE | doi:10.20944/preprints202307.0799.v1
Subject: Computer Science And Mathematics, Artificial Intelligence And Machine Learning Keywords: Swim Transformer; Resizer; CNN; structural MRI; Alzheimer’s disease
Online: 12 July 2023 (12:02:04 CEST)
Structural magnetic resonance imaging (sMRI) is widely used in the clinical diagnosis of diseases due to its advantages: high definition and noninvasive. Therefore, computer-aided diagnosis based on sMRI images is broadly applied in classifying Alzheimer’s disease (AD). Due to the excellent performance of Transformer in computer vision, Vision Transformer (ViT) has been employed for AD classification in recent years. ViT relies on access to large datasets, while the sample size of brain imaging datasets is relatively insufficient. Moreover, the pre-processing procedures of brain sMRI images are complex and labor-intensive. To overcome the limitations mentioned above, we propose Resizer Swin Transformer (RST), a deep learning model that can extract information from brain sMRI images that are only briefly processed to achieve multi-scale and cross-channel features. In addition, we pre-trained our RST on a natural image dataset and obtained better performance. The experimental results of ADNI and AIBL datasets prove that RST can achieve better classification performance in AD prediction compared with CNN-based and Transformer models.
ARTICLE | doi:10.20944/preprints202203.0180.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: seizures; epilepsy; Alzheimer’s disease; antiseizure medications; hyperexcitability
Online: 14 March 2022 (09:36:19 CET)
Epilepsy and Alzheimer's disease (AD) incidence increase with age. There are reciprocal relationships between epilepsy and AD. Epilepsy is a risk factor for AD and, in turn, AD is an independent risk factor for developing epilepsy in old age and abnormal AD biomarkers in PET and or CSF are frequently found in late onset epilepsies of unknown etiology. Accordingly, epilepsy and AD share pathophysiological processes including neuronal hyperexcitability and an early excitatory-inhibitory dysregulation leading to dysfunction in the inhibitory GABAergic and excitatory glutamatergic systems. Moreover, both β-amyloid and tau protein aggregates, the anatomopathological hallmarks of AD, have proepileptic effects. Finally, these aggregates have been found in the resection material of refractory temporal lobe epilepsies suggesting that epilepsy leads to amyloid and tau aggregates. Some epileptic syndromes, such as medial temporal lobe epilepsy share structural and functional neuroimaging findings with AD, leading to overlapping symptomatology such as episodic memory deficits and toxic synergistic effects. In this respect, the existence of epileptiform activity and electroclinical seizures in AD appears to accelerate progression of cognitive decline and the presence of cognitive decline is much more prevalent in epileptic patients than in elderly without epilepsy. Notwithstanding their clinical significance, the diagnosis of clinical seizures in AD is a challenge. Most are focal and manifest with altered level of consciousness without motor symptoms, and are often interpreted as cognitive fluctuations. Finally, despite the frequent association of epilepsy and AD dementia, there is a lack of clinical trials to guide the use of antiseizure medications (ASM). There is also a potential role for ASMs to be used as disease-modifying drugs in AD.
ARTICLE | doi:10.20944/preprints202302.0309.v1
Subject: Computer Science And Mathematics, Information Systems Keywords: Ontology; Alzheimer’s disease; Basic Formal Ontology; Interdisciplinary Research; Knowledge Sharing
Online: 17 February 2023 (09:40:53 CET)
Alzheimer’s disease is a debilitating neurodegenerative condition which is known to be the most common cause of dementia. Despite its rapidly growing prevalence, medicine still lacks a comprehensive definition of the disease. As a result, Alzheimer’s disease remains neither preventable nor curable. In recent years, broad interdisciplinary collaborations in Alzheimer’s disease research are becoming more common. Furthermore, such collaborations have already demonstrated their superiority in addressing the complexity of the disease in innovative ways. However, establishing effective communication and optimal knowledge distribution between researchers and specialists with different expertise and background is not a straightforward task. To address this challenge, we propose the Alzheimer’s disease Ontology for Diagnosis and Preclinical Classification (AD-DPC) as a tool for effective knowledge sharing in interdisciplinary/multidisciplinary teams working on Alzheimer’s disease. It covers six major conceptual groups, namely Alzheimer's disease pathology, Alzheimer's disease spectrum, Diagnostic process, Symptoms, Assessments, and Relevant clinical findings. All concepts were annotated with definitions or elucidations and in some cases enriched with synonyms and additional resources. The potential of AD-DPC to support non-medical experts is demonstrated through an evaluation of its usability, applicability and correctness. The results show that the participants in the evaluation process who lack prior medical knowledge can successfully answer Alzheimer’s disease-related questions by interacting with AD-DPC. Furthermore, their perceived level of knowledge in the field increased leading to effective communication with medical experts.
REVIEW | doi:10.20944/preprints202304.0098.v2
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s disease; Parkinson’s disease; mitochondria; oxidative stress; calcium; heterocyclic compounds
Online: 17 May 2023 (14:13:20 CEST)
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases in elderly. The key histopathological features of these diseases are the presence of abnormal protein aggregates and the progressive and irreversible loss of neurons in specific brain regions. The exact mechanisms underlying the etiopathogenesis of AD or PD remain unknown, but there is extensive evidence indicating that excessive generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) along with a depleted antioxidant system, mitochondrial dysfunction, and intracellular Ca2+ dyshomeostasis play a vital role in the pathophysiology of these neurological disorders. Due to an improvement in life expectancy, the incidence of age-related neurodegenerative diseases has significantly increased. However, there is no effective protective treatment or therapy available but rather only very limited palliative treatment. Therefore, there is an urgent need for the development of preventive strategies and disease-modifying therapies to treat AD/PD. Because dysregulated Ca2+ metabolism drives oxidative damage and neuropathology in these diseases, the identification or development of compounds capable of restoring Ca2+ homeostasis and signaling may provide a neuroprotective avenue for the treatment of neurodegenerative diseases. In addition, a set of strategies to control mitochondrial Ca2+ homeostasis and signaling has been reported, including decreased Ca2+ uptake through voltage-operated Ca2+ channels (VOCCs). In this article, we review the modulatory effects of several heterocyclic compounds on Ca2+ homeostasis and trafficking, and their ability to regulate compromised mitochondrial function and associated free radical production during the onset and progression of AD or PD. This comprehensive review also describes the chemical synthesis of the heterocycles and summarizes the clinical trial outcomes.
ARTICLE | doi:10.20944/preprints202305.0044.v2
Subject: Computer Science And Mathematics, Artificial Intelligence And Machine Learning Keywords: Federated Learning; Alzheimer’s Disease; medical imaging; MRI Image
Online: 5 May 2023 (04:49:41 CEST)
Alzheimer’s disease has become a major concern in the healthcare domain as it is growing rapidly. Many researches have been conducted to detect it from MRI images through various deep-learning approaches. However, the problem of the availability of medical data and the privacy of the patients still exists. To mitigate this issue in Alzheimer’s disease detection, we have implemented the federated approach which is found to be more efficient, robust, and consistent compared to the conventional approach. For this, we needed deep excavation on various orientations of MRI images and transfer learning architectures. Then, we utilized the publicly available two datasets (OASIS, and ADNI), and designed various cases to evaluate the performance of the federated approach. In almost all of them, the federated approach achieved better accuracy and sensitivity. In distinguishing between two classes equally, the capability of the models was better in the found model when trained with federated approach compared to the conventional approach. In this approach. MobileNet, which is a low-cost transfer learning architecture, achieved the highest 95.24%, 81.94%, and 83.97% accuracy in OASIS, ADNI, and merged (ADNI+OASIS) test set, which was way higher than the achieved performance in Conventional approach. Moreover, in this approach, only the weights of the model were shared which keeps the original MRI images in their respective hospital or institutions, mitigating the privacy concern in the healthcare domain.
REVIEW | doi:10.20944/preprints202209.0204.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Alzheimer’s disease; inflammation; non-coding RNAs; exosomes vesicles
Online: 14 September 2022 (09:20:29 CEST)
Alzheimer´s Disease (AD) has currently no effective treatment; however, preventive measures can significantly delay the progress/onset of the disease. Thus, accurate and early prediction of risk is an important strategy to alleviate the AD burden. Neuroinflammation is a major factor prompting the onset of the disease. Inflammation exerts its toxic effect via multiple mechanisms. Amongst others, it is affecting gene expression via modulation of non-coding RNAs (ncRNAs), such as miRNAs. Recent evidence supports that inflammation can also affect long non-coding RNAs (lncRNAs) expression. While the association between miRNAs and inflammation in AD has been extensively studied, the role of lncRNAs in neurodegenerative diseases has been less explored. In this review, we focus on lncRNAs and inflammation in the context of AD. Furthermore, since plasma-isolated extracellular vesicles (EVs) are increasingly recognized as an effective monitoring strategy of brain pathologies, we have focused on the studies reporting dysregulated lncRNAs in EVs isolated from AD patients and controls. The revised literature shows a positive association between pro-inflammatory lncRNAs and AD. However, the reports evaluating lncRNAs alterations in EVs isolated from plasma of patients and controls, although still limited confirm the value of specific lncRNAs associated with AD as reliable biomarkers. This is an emerging field that will open new avenues to improve risk prediction, patients’ stratification and may lead to the discovery of potential novel therapeutic targets for AD
REVIEW | doi:10.20944/preprints202206.0302.v1
Subject: Medicine And Pharmacology, Pathology And Pathobiology Keywords: Neuroproteomics; Alzheimer’s disease biomarker; neurodegeneration
Online: 22 June 2022 (03:44:49 CEST)
Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by progressive cognitive decline. The two cardinal neuropathological hallmarks of AD include buildup of cerebral β amyloid (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau. The current disease-modifying treatments are still not effective enough to lower the rate of cognitive decline. The paucity of early detection and disease progression biomarkers also seems to present a major obstacle to AD drug development. The current established readouts based on expression levels of amyloid beta, tau and phospho tau have shown many discrepancies in patient samples when linked to disease progression. There is an urgent need to identify diagnostic and disease progression biomarkers from blood, CSF or other biofluids that can facilitate early detection of the disease and provide pharmacodynamic readouts for new drugs being tested in clinical trials. Advances in proteomic approaches using state-of-the-art mass spectrometry, are now being increasingly applied to study AD disease mechanisms, identify drug targets and novel disease biomarkers. In this report, we describe applications of the quantitative proteomic approaches for understanding AD pathophysiology, summarize the current knowledge gained from proteomic investigations of AD and discuss development and validation of new predictive and diagnostic disease biomarkers.
REVIEW | doi:10.20944/preprints202311.0079.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s disease; Cognitive Impairment; Blood biomarkers; Cognitive functions; Cognition.
Online: 1 November 2023 (12:00:12 CET)
Blood biomarkers represent a promising future for studying cognitive impairment, particularly in Alzheimer's Disease (AD), as they offer a non-invasive alternative to cerebrospinal fluid tests and have potential as population screening tools. However, the relationships between these biomarkers and specific cognitive functions, as well as their utility in predicting longitudinal cognitive decline, are not yet fully understood. This descriptive review surveys the literature from 2018 to 2023, focusing on the associations between Amyloid-β, Total Tau, Phosphorylated Tau (p-tau), Neurofilament Light (Nfl), and Glial Fibrillary Acidic Protein (GFAP) with cognition. The reviewed studies are heterogeneous, varying in design and population (mixed, cognitively impaired, or unimpaired), and show results that are sometimes conflicting. Generally, cognition positively correlates with Aβ levels, especially when evaluated through the Aβ42/Aβ40 ratio. In contrast, Tau, Nfl, and GFAP levels typically show a negative correlation with cognitive performance. While p-tau measures tend to show stronger associations with cognitive functions than other biomarkers, no single blood marker has emerged as predominantly associated with a specific cognitive domain. These findings add to our understanding of the complex relationship between blood biomarkers and cognitive performance and underscore their potential utility in clinical evaluations of cognition.
REVIEW | doi:10.20944/preprints202110.0231.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Alzheimer’s disease; magnetic resonance imaging; animal model; amyloid-beta
Online: 15 October 2021 (15:06:55 CEST)
Amyloid-beta plays an important role in the pathogenesis of Alzheimer’s disease. Aberrant amyloid-beta and tau accumulation induce neuroinflammation, cerebrovascular alterations, synaptic deficits, functional deficits, and neurodegeneration, leading to cognitive impairment. Animal models recapitulating the amyloid-beta pathology such as transgenic, knock-in mouse and rat models have facilitated the understanding of disease mechanisms and development of therapeutics targeting at amyloid-beta. There is a rapid advance in high-field MR in small animals. Versatile high-field magnetic resonance imaging (MRI) sequences such as diffusion tensor imaging, arterial spin labelling, resting-state functional MRI, anatomical MRI, MR spectroscopy as well as contrast agents have been developed for the applications in animal models. These tools have enabled high-resolution in vivo structural, functional, and molecular readouts with a whole brain field-of-view. MRI have been utilized to visualize non-invasively the amyloid-beta deposits, synaptic deficits, regional brain atrophy, impairment in white matter integrity, functional connectivity, cerebrovascular and glymphatic system in animal models of amyloidosis. Many of the readouts are translational in clinical MRI in the brain of patients with Alzheimer’s disease. In this review, we summarize the recent advance of using MRI for visualizing the pathophysiology in amyloidosis animal model. We discuss the outstanding challenges in brain imaging using MRI in small animal and propose future outlook in visualizing amyloid-beta-related alterations in brain of animal models.
REVIEW | doi:10.20944/preprints201804.0233.v1
Subject: Medicine And Pharmacology, Psychiatry And Mental Health Keywords: Alzheimer’s Disease; network medicine; inflammation; network and system pharmacology; traditional Chinese medicine
Online: 18 April 2018 (07:41:00 CEST)
Alzheimer’s Disease (AD) is a neurodegenerative condition that currently has no known cure. The principles of the expanding field of network medicine (NM) have recently been applied to AD research. The main principle of NM proposes that diseases are much more complicated than one mutation in one gene, and incorporate different genes, connections between genes, and pathways that may include multiple diseases to create full scale disease networks. AD research findings as a result of the application of NM principles have suggested that functional network connectivity, myelination, myeloid cells, and genes and pathways may play an integral role in AD progression, and may be integral to the search for a cure. Different aspects of the AD pathology could be potential targets for drug therapy to slow down or stop the disease from advancing, but more research is needed to reach definitive conclusions. Additionally, the holistic approaches of network pharmacology in traditional Chinese medicine (TCM) research may be viable options for the AD treatment, and may lead to an effective cure for AD in the future.
ARTICLE | doi:10.20944/preprints202307.2120.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s disease, Medicinal mushroom, Amyloid β, Zinc, 5XFAD
Online: 31 July 2023 (11:31:23 CEST)
Alzheimer's disease (AD) is characterized by memory impairment and existence of amyloid-β (Aβ) plaques and neuroinflammation. Due to the pivotal role of oxidative damage in AD, natural antioxidative agents, such as polyphenol-rich fungi, have garnered scientific scrutiny. Here, the aqueous extract of mixed medicinal mushroom mycelia (MMMM) - Phellinus linteus, Ganoderma lucidum, and Inonotus obliquus - cultivated on a barley medium, was assessed for its anti-AD effects. A neuron-like PC12 cells, which were subjected to Zn2+, an Aβ aggregator, was employed as an in vitro AD model. The cells pretreated with or without MMMM assayed for Aβ immunofluorescence, cell viability, reactive oxygen species (ROS), apoptosis, and antioxidant enzyme activity. 5XFAD mice were administered with 30 mg/kg/day MMMM for 8 weeks and underwent memory function tests and histologic analyses. In vitro results demonstrated that the cells pretreated with MMMM exhibited attenuation in Aβ immunofluorescence, ROS accumulation, and apoptosis, and increment in cell viability and antioxidant enzyme activity. In vivo results revealed that 5XFAD mice administered with MMMM showed attenuation in memory impairment and histologic deterioration such as Aβ plaques accumulation and neuroinflammation. MMMM might mitigate AD-associated memory impairment and cerebral pathologies, including Aβ plaque accumulation, and neuroinflammation, by impeding Aβ-induced neurotoxicity.
HYPOTHESIS | doi:10.20944/preprints202306.0807.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s disease; beta-amyloid toxicity; amyloid deposits; cellular uptake; lysosome
Online: 13 June 2023 (03:27:48 CEST)
Amyloid degradation toxicity hypothesis is the integrative theory of Alzheimer’s disease (AD). It successfully interprets phenomena and paradoxes associated with AD pathobiology. The hypothesis explains the limitations of currently used biomarkers of AD and proposes etiology-related parameters. These parameters could be measured in humans and become novel diagnostic and prognostic clinical tools. Based on the proposed framework, we foresee the development of effective medications to treat, stall the progression of, or prevent the development of the disease. The promise is supported by published preclinical data. This manuscript summarizes the amyloid degradation toxicity hypothesis of Alzheimer’s disease at different levels of organization.
REVIEW | doi:10.20944/preprints202211.0042.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s Disease; Parkinson’s Disease; eye movements; Rough Set; Machine Learning
Online: 2 November 2022 (04:12:08 CET)
Humans are a vision-dominated species, and what we see depends on where we look. Therefore, eye movements (EM) are essential to our interactions with the environment, and experimental findings show EM is affected in neurodegenerative disorders (ND). It could be a reason for some cognitive and movement disorders in ND. Therefore, we aim to determine if changes in EM-evoked responses can tell us about ND, such as Alzheimer’s (AD) and Parkinson’s Disease (PD) progression in different stages. In the present review, we have analyzed the results of neurological, psychological, and EM (saccades, antisaccades, pursuit) tests to predict disease progression with Machine Learning (ML) methods. Described predictive algorithms are using various approaches, including Granular Computing, Naive Bayes, Decision Trees/Tables, Logistic Regression, C-/LinearSVC, KNC, and Random Forest. We demonstrated that EM is a robust biomarker for assessing symptom progression in PD and AD. There are also navigation problems in 3D space in both diseases. Consequently, we investigated EM experiments in the virtual space and how they may help find neurodegeneration-related brain changes. In conclusion: EM parameters with clinical symptoms are powerful precision instruments that, in addition to predictions of ND progression with the help of ML, could be used to indicate the different preclinical stages of both diseases.
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s disease; artificial intelligence; clinical trials; eligibility assessment; randomization
Online: 8 October 2021 (11:31:14 CEST)
Clinical trials for Alzheimer’s disease (AD) face multiple challenges, such as the high screen failure rate and even allocation of heterogeneous participants. Artificial intelligence (AI), which has become a potent tool of modern science with the expansion in the volume, variety, and velocity of biological data, offers promising potential to address these issues in AD clinical trials. In this review, we introduce the current status of AD clinical trials and topic of machine learning. Then, a comprehensive review is focused on the potential applications of AI in the steps of AD clinical trials, including the prediction of AD biomarkers and differential diagnosis of AD in the prescreen during eligibility assessment and the likelihood stratification of patients who will progress to AD dementia and fast cognitive decline group from the slow decline group in randomization. Finally, this review provides challenges, developments and the future outlook on the integration of AI into AD clinical trials.
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: Hypoxia Inducible Factor; HIF; Ischemia; Hypoxia; Adaptation; Alzheimer’s Disease; Parkinson Disease; Neurodegeneration
Online: 26 February 2021 (15:34:31 CET)
Hypoxia is one of the most common pathological conditions which results from ischemic injury, trauma, inflammatory conditions, tumors, The adaptation of the body to hypoxia is a phenomenon that is of great importance both in normal conditions and in Most of the cellular response’ reactions to hypoxia is associated with a family of transcription factors called hypoxia-inducible factors (HIF). They induce the expression of a wide range of genes that help cells adapt to a hypoxic HIF functions are currently being extensively studied. In 2019, William G. Kaelin and Gregg Semenza from the USA and Sir Peter J. Ratcliffe from the UK received the Nobel Prize in Physiology or Medicine for the discovery of the basic mechanisms of adaptation to hypoxia and investigation of the role of HIF factor in the regulation of the hormone erythropoietin Based on its pivotal physiological importance, the HIF factor attracts more and more attention as a new potential target for treating a large number of diseases associated with Most of the experimental work dealing with the HIF factor is focused on its role in liver and However, increasing amount of experimental results clearly demonstrates that the HIF factor-based response represents an universal adaptation mechanism for all kinds of tissues, including the nervous system where HIF is critical for regulating neurogenesis, nerve cell differentiation, and neuronal This review provides actual overview about the complex role of HIF-1 in the adaptation of nerve cells to hypoxia with the focus on its potential role by various neuronal
REVIEW | doi:10.20944/preprints202101.0184.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Alzheimer’s Disease; antibacterial; anti-biofilm; antifungal; antiviral; bacteria; infectious burden; parasites; pathogens; viruses
Online: 11 January 2021 (11:28:10 CET)
Alzheimer’s disease (AD) is a chronic neurodegenerative disease associated with the overproduction and accumulation of amyloid-β peptide and hyperphosphorylation of tau proteins in the brain. Despite extensive research on the amyloid-based mechanism of AD pathogenesis, the underlying cause of AD remains poorly understood. No disease-modifying therapies currently exist, and numerous clinical trials have failed to demonstrate any benefits. The recent discovery that the amyloid-β peptide has antimicrobial activities supports the possibility of an infectious aetiology of AD and suggests that amyloid-β plaque formation might be induced by infection. AD patients have a weakened blood-brain barrier and immune system and are thus at elevated risk of microbial infections. Such infections can cause chronic neuroinflammation, production of the antimicrobial amyloid-β peptide, and neurodegeneration. Various pathogens, including viruses, bacteria, fungi, and parasites have been associated with AD. Most research in this area has focused on individual pathogens, with herpesviruses and periodontal bacteria being most frequently implicated. The purpose of this review is to highlight the potential role of multi-pathogen infections in AD. Recognition of the potential coexistence of multiple pathogens and biofilms in AD's aetiology may stimulate the development of novel approaches to its diagnosis and treatment. Multiple diagnostic tests could be applied simultaneously to detect major pathogens, followed by anti-microbial treatment using antiviral, antibacterial, antifungal, and anti-biofilm agents.
REVIEW | doi:10.20944/preprints202101.0062.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Alzheimer’s disease (AD); aggregation; autophagy; aggresome; autophagosomes; aggrephagy
Online: 4 January 2021 (16:35:17 CET)
Alzheimer’s disease (AD) is one of the most prevailing neurodegenerative diseases in the world, which is characterized by memory dysfunction and the formation of tau and amyloid β (Aβ) aggregate in multiple brain regions, including the hippocampus and cortex. The formation of senile plaques involving tau hyperphosphorylation, fibrillar Aβ, and neurofibrillary tangles (NFTs) are used as pathological markers of AD, and eventually produces aggregation or misfolded protein. Importantly, it has been found that failure to degrade these aggregate-prone proteins leads to pathological consequences, such as synaptic impairment, cytotoxicity, neuronal atrophy, and memory deficits associated with AD. Recently, increasing evidences have been suggested that autophagy pathway plays a role as a central cellular protection system to prevent the toxicity induced by aggregate or misfolded proteins. Moreover, it has also been related that AD-related protein aggresomes could be selectively degraded by autophagosome and lysosomal fusion through autophagy pathway which is known as aggrephagy. Therefore, the regulation of autophagy might be served as a useful approach to modulate the formation of aggresome associated in AD. This review focuses on the recent improvements in the application of natural compounds and small molecules as a potential therapeutic approach for AD prevention and treatment via aggrephagy.
ARTICLE | doi:10.20944/preprints201805.0070.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Hyperpolarized gas MRI; xenon; gas retention; Alzheimer’s disease; wash out; vascular
Online: 3 May 2018 (12:02:44 CEST)
Biomarkers have the potential to aid in the study of Alzheimer’s disease (AD); unfortunately, AD biomarker values often have a high degree of overlap between healthy and AD individuals. This study investigates the potential utility of a series of novel AD biomarkers, the sixty second 129Xe retention time, and the xenon washout parameter, based on the washout of hyperpolarized 129Xe from the brain of AD participants following inhalation. The xenon washout parameter is influenced by cerebral perfusion, T1 relaxation of xenon, and the xenon partition coefficient, all factors influenced by AD. Participants with Alzheimer’s disease (n=4) and healthy volunteers (n=4) were imaged using hyperpolarized 129Xe magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to determine the amount of retain xenon in the brain. At 60 sec post breath hold, AD patients retained significantly higher amounts of 129Xe compared to healthy controls. Data was fit to a pharmacokinetic model and the xenon washout parameter was extracted. Xenon washout in white and grey matter occurs at a slower rate in Alzheimer’s participants (129Xe half-life time of 42s and 43s, respectively) relative to controls (20s and 16s, respectively). Following larger scale clinical trials for validation, the xenon washout parameter has the potential to become a useful biomarker for the support of an AD diagnosis.
HYPOTHESIS | doi:10.20944/preprints202108.0454.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s disease; DNA damage; somatic mutation; integrin; synaptic adhesion
Online: 23 August 2021 (14:34:00 CEST)
Alzheimer’s disease (AD) is a genetically complex senile neurodegeneration with unknown etiology. The first gene discovered to be mutated in early-onset AD, the amyloid precursor protein (APP), has been widely assumed as a causal factor in the disease cascade due to its generation of Aβ species. APP has an evolutionarily conserved biological role and activates a signaling program with notable similarities to integrin—a cell adhesion receptor with a wide array of functions. Intriguingly, several AD genome-wide association study (GWAS) candidate genes, including the SHARPIN locus recently reported by us and others, influence signaling of the integrin pathway. Integrins are focal adhesion regulators and serve in nervous system development, synaptic plasticity, and Tau phosphorylation. These observations suggest that the function of APP probably goes beyond Aβ generation in AD. Aging—the strongest risk factor for AD—is associated with various clock-like events in cells. For instance, neurons are continuously impacted by stochastic ‘hits’ to their genomes in aging, in the forms of DNA damage, insertion-deletions, copy-number variations (CNVs) and other types of somatic mutations. DNA damage and somatic mutations can result in neoplastic changes and cancer in mitotically active cells. However, their consequences in post-mitotic cells such as aging neurons are less defined. The current hypothesis holds that the stochastic loss of DNA sequence data at random loci in aging affects longer genes by chance more frequently. As a result, the biological processes coordinated by long genes may be more vulnerable to such random aging effects. Curiously, as shown by us and others, long genes are strongly enriched for synapse- and cell adhesion-related ontologies, more than any other biological process or cellular compartment. In addition, among various cell types, neurons possess the highest levels of long gene expression and are therefore more vulnerable to such harmful effects. The long gene vulnerability hypothesis provides a simple link between aging and the genetic landscape of AD and warrants new strategies for disease modification.
CONCEPT PAPER | doi:10.20944/preprints202306.0809.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: Alzheimer’s disease; Parkinson’s disease; condensed cytokines; intrathecal; PRP
Online: 12 June 2023 (09:12:30 CEST)
Choroid plexus insufficiency or glymphatic stasis are often classified as prequels to harmful accretion of toxic proteins in neurodegenerative disease. Cognitive decline and memory loss subsequently become cardinal features of Alzheimer’s disease (AD), typically progressing with amyloid-ß and tau protein accumulation. For Parkinson’s disease (PD), α-synuclein deposits and dopamine depletion are linked to impaired movement, resting tremor, and rigidity. Importantly, both diagnoses are accompanied by hyperinflammation and intrathecal cytokine changes. Thus far, numerous clinical trials for investigational drugs have produced nothing effective for AD or PD, yet the anti-inflammatory and regenerative potential of platelet-rich plasma (PRP) remains largely unexamined in this context. This report explores a proposed Phase I study on intrathecal condensed plasma growth factors processed from autologous thrombin-activated PRP as monotherapy for AD or PD. The concept gains support from related work where cytokines of platelet origin successfully lowered inflammation, corrected background fibrosis, deactivated abnormal cells, and recovered local tissue function—all desirable outcomes in AD and PD. PRP-mediated effects on membrane potentials, electrolyte balance, and water clearance are less well characterized, but experimental evidence suggests these pathways could likewise influence glymphatic drainage to ameliorate proteinopathies. As a well-tolerated ‘orthobiologic’ with no hypersensitivity risk, intrathecal PRP and its derivatives bring advantages distinct from synthetic pharmaceuticals. If age-associated neuroinflammation in AD and PD is an upstream event contributing to neural disruption, then dampening local oxidative stress by a patient’s own platelet cytokines (as already proven in other tissues) could offer therapeutic relevance to these neurodegenerative conditions as well.
REVIEW | doi:10.20944/preprints201808.0410.v1
Subject: Chemistry And Materials Science, Analytical Chemistry Keywords: metabolomics; direct mass spectrometry; Alzheimer’s disease; pathogenesis; biomarkers
Online: 23 August 2018 (10:10:47 CEST)
Direct mass spectrometry-based metabolomics has been widely employed in the last years to characterize metabolic alterations underlying to Alzheimer’s disease development and progression. This high-throughput approach presents a great potential for fast and simultaneous fingerprinting of a vast number of metabolites, which can be applied to multiple biological samples such as serum/plasma, urine, cerebrospinal fluid and tissues. In this review article we present the main advantages and drawbacks of metabolomics based on direct mass spectrometry compared with conventional analytical techniques, and provide a comprehensive revision of the literature on the application of these tools in Alzheimer’s disease research.
REVIEW | doi:10.20944/preprints202211.0032.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s disease; Quantum Dot Nanoparticles; PINK1; Theranostic; mitochondria; drug delivery
Online: 1 November 2022 (14:29:26 CET)
One of the most frequent brain diseases, Alzheimer's is defined by poor cognitive function brought on by the build-up of Beta Amyloid plaques and the gradual death of neurons. Glucose metabolism and the development of amyloid plaques are being studied together. Under physiologically normal circumstances, glucose is the primary substrate for the adult human brain. The prodromal phases of AD are significantly influenced by glucose hypometabolism. Hypometabolism of glucose in the brain is a clear sign of mitochondrial dysfunction and bioenergetic system impairment. By regulating energy synthesis and cell death, mitochondria play a crucial role in the functioning of cells. Increased formation of reactive oxygen species (ROS) and oxidative stress are a result of mitochondrial dysfunction, which also accelerates the development of Alzheimer's disease. For the maintenance of balance, autophagy is crucial because it selectively destroys damaged mitochondria. AD affects this route for mitochondrial breakdown. Targeting specific mitochondrial ligands by interventions along this pathway might be a useful therapeutic approach. Due to a number of biological obstacles, this method has significant limitations. As a result, many nanocarriers have been created to improve drug delivery effectiveness. All potential nanotechnology-based treatments for AD have been examined in this study, with a particular emphasis on medication delivery to the mitochondria
REVIEW | doi:10.20944/preprints202108.0518.v2
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: liquid biopsy; circulating biomarkers; Alzheimer’s disease; neurodegeneration; cell-free; diagnosis
Online: 8 March 2022 (09:56:01 CET)
Alzheimer’s disease is the most common neurodegenerative disease and affects persons of all races, ethnic groups, and sexes. The disease is characterized by neuronal loss leading to cognitive decline and memory loss. There is no cure and the effectiveness of existing treatments is limited and depends on the time of diagnosis. The long prodromal period, during which patients’ ability to live a normal life is not affected despite neuronal loss, often leads to a delayed diagnosis because it can be mistaken for normal aging of the brain. In order to make a substantial impact on AD patients, early diagnosis may provide a greater therapeutic window for future therapies to slow AD-associated neurodegeneration. Current gold standards for disease detection include magnetic resonance imaging and positron emission tomography scans, which visualize amyloid β and phosphorylated tau depositions and aggregates. Liquid biopsies, already an active field of research in precision oncology, are hypothesized to provide early disease detection through minimally or non-invasive sample collection techniques. Liquid biopsies in Alzheimer’s disease have been studied in cerebrospinal fluid, blood, ocular, oral, and olfactory fluids. However, most of the focus has been on blood and cerebrospinal fluid due to biomarker specificity and sensitivity attributed to the effects of the blood-brain barrier and inter-laboratory variation during sample collection. Many studies have identified amyloid β and phosphorylated tau levels as putative biomarkers, however, advances in next-generation sequencing-based liquid biopsy methods have led to significant interest in identifying nucleic acids species associated with Alzheimer’s disease from liquid tissues. Differences in cell-free RNAs and DNAs have been described as potential biomarkers for AD and hold the potential to affect disease diagnosis, treatment, and future research avenues.
REVIEW | doi:10.20944/preprints202012.0059.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Alzheimer’s disease; mitochondrial dysfunctions; phytochemicals; reactive oxygen species (ROS); autophagy
Online: 2 December 2020 (11:14:07 CET)
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a decline in cognitive function with neuronal damage. Although the precise pathobiology of AD is still elusive, accumulating evidences suggest that mitochondrial dysfunction is one of the underlying causes of AD. Mutations of mitochondrial or nuclear DNA that encode mitochondrial constituents may cause mitochondrial dysfunctions. In particular, dysfunction of electron transport chain complexes along with interactions of mitochondrial pathological proteins are associated with mitochondrial dysfunctions in AD. Mitochondrial dysfunction causes an imbalance in reactive oxygen species, leading to oxidative stress (OS) and vice-versa. Neuroinflammation is another potential contributory factor to induce mitochondrial dysfunction. Phytochemicals or other natural compounds have the potential to scavenge oxygen free radicals and enhance cellular antioxidant defense system, and thereby protect against OS-mediated cellular damage. Phytochemicals can also modulate other cellular processes, including autophagy and mitochondrial biogenesis. Pharmacological intervention through neuroprotective phytochemicals can, therefore, be a potential strategy to combat mitochondrial dysfunctions as well as AD. This review focuses on the role of phytochemicals to mitigate mitochondrial dysfunction in the therapy of AD pathogenesis.
REVIEW | doi:10.20944/preprints202307.1514.v1
Subject: Medicine And Pharmacology, Medicine And Pharmacology Keywords: Vanadium; Alzheimer’s disease; diabetes; insulin resistance; mitochondrial; oxidative phosphorylation
Online: 21 July 2023 (11:30:52 CEST)
Vanadium is a well-known essential trace element, which usually exists in oxidation states in form of vanadate cation intracellularly. The pharmacological study of vanadium begins at the discovery of its unexpected inhibitory effect on ATPase. Thereafter, the protective effects on cells and the abilities in glucose metabolism regulation were observed from vanadium compound, leading to the application of vanadium compounds in clinical trials for curing diabetes. Alzheimer’s dis-ease (AD) is the most common dementia disease in elderly people. However, there is still no efficient agents for treating AD safely to date. This is mainly because of the complexity of the pathology, which are characterized by the senile plaques composed by amyloid-beta (Aβ) protein in the parenchyma of brain and the neurofibrillary tangles (NFTs) derived from hyperphosphorylated tau protein in neurocyte, along with mitochondrial damage, and eventually the central nervous system (CNS) atrophy. AD was also illustrated as type-3 diabetes, because of the observations of insulin deficiency and the high level of glucose in cerebrospinal fluid (CSF), as well as the im-paired insulin signaling in brain. In this review, we summarized the advance of applicating vanadium compound on AD treatment in experimental research and pointed out the limitation of the current study on using vanadium compounds in AD treatment. We hope it will help the future study in this field.
HYPOTHESIS | doi:10.20944/preprints202012.0813.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Alzheimer’s disease; beta-amyloid; protease; membrane; membrane channel; lysosome; autophagy; mitochondrion
Online: 31 December 2020 (13:32:26 CET)
Alzheimer's disease (AD) is the most common cause of dementia and affects millions of people around the world. Neuronal death in AD is initiated by the toxic action of oligomeric amyloid-β (Aβ) peptides. The formation of membrane channels by Aβ is a primary molecular action and does not require any other proteins. Channels are formed by short amyloid fragments faster and more frequently than by full-length peptides. The channel formation is dependent on an electrostatic interaction between a positively charged peptide and a negatively charged membrane. Negative membranes can be found in several locations of a cell – the inner leaflet of plasma membrane, mitochondria, and lysosomes, which all are well-known cellular targets in AD. Considering that the amyloid enters a cell by endocytosis and is exposed to lysosomal enzymes, we propose the amyloid degradation toxicity hypothesis. Endopeptidases degrade the endocytosed peptide. Produced fragments form membrane channels, which can transfer various ions (including protons) and even relatively large compounds. The neutralization of lysosomal content inactivates enzymes, which fails the whole system of recycling cellular content, including autophagy. The permeabilization of lysosomes could also lead to cell death through necrotic and apoptotic mechanisms. We discuss several mechanisms that describe how amyloid degradation products reach plasma and mitochondrial membranes, and form membrane channels. The pathogenesis of AD is discussed at various levels in a context of how the primary molecular mechanism of membrane channel formation could progress into the disease state. The discussion starts at the molecular level and extends to why the development of a disease takes years and is closely associated with aging. The proposed hypothesis offers an interpretation to several clinical observations such as the involvement of iron metabolism and an inverse association between developing Alzheimer's disease and cancer. Predictions about potential biomarkers and effectiveness of future treatments are discussed.
BRIEF REPORT | doi:10.20944/preprints202306.1200.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: hippocampus; Alzheimer’s disease; neuroinflammation; insulin signal; phytohormones; neurotrophic factor; neuroprotector
Online: 16 June 2023 (08:55:50 CEST)
Strong evidence indicates that insulin resistance contributes to the development of Alzheimer´s disease by promoting inflammation, oxidative stress, and blood vessel damage. Conversely, neuroinflammation induces insulin resistance by targeting insulin signaling molecules: the insulin receptor substrates 1 and 2 (IRS1/2). In addition, neuroinflammation is strongly linked to reduced levels of brain-derived neurotrophic factor (BDNF) expression. BDNF is a key factor for neuronal survival, and its expression is compromised in neurodegenerative disorders. In this study, we show that, in a triple-transgenic (3xTg) mice model of Alzheimer’s disease, the BDNF and IRS2 but not the IRS1 mRNA expression levels were reduced in the hippocampus, together with higher levels of TNFα, compared with wild-type mice. Subgroups of control and 3xTg mice received short and long treatments of Abscisic Acid (ABA), a phytohormone with anti-inflammatory and insulin-sensitizing capabilities. We found that the short ABA treatment can increase the IRS1 and IRS2 mRNA expression both in wild-type and 3xTg mice, concomitant with reducing pro-inflammatory cytokine TNFα in 3xTg mice. However, earlier, and thus longer treatments are required to rescue the BDNF mRNA levels. Our data strongly confirm that ABA administration is a potential treatment to prevent Alzheimer´s disease, via lowering neuroinflammation, potentially rescuing insulin signaling molecules and BDNF mRNA expression.
REVIEW | doi:10.20944/preprints202106.0471.v2
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s Disease; microfluidics; lab-on-chip; 3D culture; organ-on-chip
Online: 23 August 2021 (13:38:28 CEST)
Alzheimer’s disease (AD) is a significant health concern worldwide with enormous social and economic impact globally. The gradual deterioration of cognitive functions and irreversible neuronal losses are primary features of the disease. Even after decades of research, most therapeutic options are merely symptomatic, and drugs in clinical practice present numerous side effects. Lack of effective diagnostic techniques prevents the early prognosis of disease, resulting in a gradual deterioration in the quality of life. Furthermore, the mechanism of cognitive impairment and AD pathophysiology is poorly understood. Microfluidics exploits different microscale properties of fluids to mimic environments on microfluidic chip-like devices. These miniature multichambered devices can be used to grow cells and 3D tissues in vitro, analyze cell-to-cell communication, decipher the roles of neural cells like microglia, and gain insights into AD pathophysiology. This review focuses on the applications and impact of microfluidics on AD research. We discuss the technical challenges and possible solutions provided by this new cutting-edge technique to understand disease-associated pathways and mechanisms.
ARTICLE | doi:10.20944/preprints202008.0091.v1
Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: induced pluripotent stem cells; disease modelling; neuronal differentiation; cholinergic neurons; Alzheimer’s disease; frontotemporal dementia
Online: 4 August 2020 (11:17:44 CEST)
The study of neurodegenerative diseases using pluripotent stem cells requires new methods to assess neurodevelopment and neurodegeneration of specific neuronal subtypes. The cholinergic system, characterized by its use of the neurotransmitter acetylcholine, is one of the first to degenerate in Alzheimer’s disease and is also affected in frontotemporal dementia. We developed a differentiation protocol to generate basal forebrain cholinergic neurons (BFCNs) from induced pluripotent stem cells (iPSCs) aided by the use of small molecule inhibitors and growth factors. Ten iPSC lines were successfully differentiated into BFCNs using this protocol. The neuronal cultures were characterised through RNA and protein expression, and functional analysis of neurons was confirmed by whole-cell patch clamp. We have developed a reliable protocol using only small molecule inhibitors and growth factors, while avoiding transfection or cell sorting methods, to achieve a BFCN culture that expresses the characteristic markers of cholinergic neurons.
ARTICLE | doi:10.20944/preprints202105.0018.v1
Subject: Computer Science And Mathematics, Algebra And Number Theory Keywords: Ambient Intelligence; Internet of Things; Context; Prediction; Context Histories; Alzheimer’s Disease
Online: 4 May 2021 (13:47:01 CEST)
The new Internet of Things (IoT) applications are enabling the development of projects that help monitoring people with different diseases in their daily lives. Alzheimer’s is a disease that affects neurological functions and needs support to maintain maximum independence and security of patients during this stage of life, as the cure and reversal of symptoms have not yet been discovered. The IoT-based monitoring system provides the caregivers’ support in monitoring people with Alzheimer’s Disease (AD). This paper presents an ontology-based computational model which receives physiological data from external IoT applications, allowing to identify of potentially dangerous behaviors for patients with AD. The main scientific contribution of this work is the specification of a model focusing on Alzheimer’s disease using the analysis of Context Histories and Context Prediction, which considering the state of the art, it is the only one that uses analysis of Context Histories to perform predictions. The research also proposes a simulator to generate activities of the daily life of patients allowing the creation of datasets. These datasets were used to evaluate the contributions of the model and were generated according to the standardization of the ontology. The simulator generated 1025 scenarios applied to guide the predictions, which achieved average accurary of 97.44%. The experiments also allowed the learning of 20 relevant lessons on technological, medical and methodological aspects of DCARE that are recorded in this article.
ARTICLE | doi:10.20944/preprints201909.0308.v1
Subject: Medicine And Pharmacology, Other Keywords: Alzheimer’s disease; emphasis learning; multi-modal classification; svm; pca
Online: 27 September 2019 (10:26:34 CEST)
A method for classification is introduced in this article, and it is tested on ADNI database to diagnose alzheimer’s disease (AD). It is obvious that tunning the performance of a classification to get better results is a complicated problem, and when we want model’s accuracy or other peformance measurments higher than 90%, the problem will be more complicated. In this study, we tried and succeeded to discover a method to solve this problem. The final feature set can be used clustering too, because outgrowth feature set of the proposed method is invigorated. In the recent years, a lot of activities is done to develop computer aided systems (CAD) for alzheimer’s disease diagnosis. Most of these recently developed systems concenterated on extracting and combining features from MRI, PET, CSF, and …; in this article, we made attempt to do so and utilized one more technique to increase classification performance. Finding and producing the best features to solve three binary classiﬁcation problems of AD vs. Normal Control (NC), Mild Cognitive Impairment (MCI) vs. NC, and MCI vs. AD are the purposes of this article. Experiments indicate performance and effectiveness rates of the proposed method, which are accuracies of 98.81%, 81.61%, and 81.40% for AD vs. NC, MCI vs. NC, and AD vs. MCI classification problems, respectively. As can be seen, using this method increased the performance of the three binary problems incredibly.
REVIEW | doi:10.20944/preprints202311.0227.v1
Subject: Biology And Life Sciences, Aging Keywords: apolipoprotein E; Alzheimer’s disease; methylation; dementia; epigenetics; tau protein; amyloid-β; longevity
Online: 3 November 2023 (10:00:30 CET)
Sporadic Alzheimer’s disease (AD) derives from an interplay among environmental factors and genetic variants, while epigenetic modifications have been expected to affect the onset and progression of its complex etiopathology. Heterozygous carriers of the apolipoprotein E gene (APOE)4 allele have a 4-fold increased risk of developing AD, while APOE 4/4-carriers have a 12-fold increased risk in comparison with the APOE 3-carriers. The main longevity factor is the homozygous APOE ε3/ε3 genotype. In the present narrative review article, we summarized and described the role of APOE epigenetics in aging and AD pathophysiology. It is not fully understood how APOE variants may increase or decrease AD risk, but this gene is known to affect amyloid- and tau-mediated neurodegeneration directly or indirectly, also by affecting lipid metabolism and inflammation. For sporadic AD, epigenetic regulatory mechanisms may control and influence APOE expression in response to external insults. Diet, a major environmental factor, has been significant associated with physical exercise, cognitive function, and the methylation level of several cytosine-phosphate-guanine (CpG) dinucleotides sites of APOE.
ARTICLE | doi:10.20944/preprints202306.1450.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s disease; blood-brain barrier; metabolic phenotype; sleep behavior; Promethion cages; oleocanthal
Online: 20 June 2023 (14:31:29 CEST)
Aging is a major risk factor for Alzheimer's disease (AD). AD mouse models are frequently used to assess pathology, behavior, and memory in AD research. While the pathological characteristics of AD are well established, our understanding of the changes in the metabolic phenotypes with age and pathology is limited. In this work, we used the Promethion cage systems® to monitor changes in physiological metabolic and behavioral parameters with age and pathology in wild-type and 5xFAD mouse models. Then, we assessed whether these parameters could be altered by treatment with oleocanthal, a phenolic compound with neuroprotective properties. Findings demonstrated metabolic parameters such as body weight, food and water intake, energy expenditure, dehydration, and respiratory exchange rate, and the behavioral parameters of sleep patterns and anxiety-like behavior are altered by age and pathology. However, the effect of pathology on these parameters was significantly greater than normal aging, which could be linked to amyloid-β deposition and blood-brain barrier (BBB) disruption. In addition, and for the first time, our findings suggest an inverse correlation between sleep hours and BBB breakdown. Treatment with oleocanthal improved the assessed parameters and reduced anxiety-like behavior symptoms and sleep disturbances. In conclusion, aging and AD are associated with metabolism and behavior changes, with the changes being greater with the latter, which were rectified by oleocanthal. In addition, our findings suggest that monitoring changes in metabolic and behavioral phenotypes could provide a valuable tool to assess disease severity and treatment efficacy in AD mouse models.
REVIEW | doi:10.20944/preprints202010.0195.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Autophagy; Amyloid precursor protein (APP); β‐amyloid (Aβ); mTOR; Alzheimer’s disease (AD).
Online: 9 October 2020 (11:07:53 CEST)
Autophagy refers to the degradation of cytoplasmic constituents by a lysosomal-mediated pathway, which plays a critical role in maintaining cellular homeostasis. Importantly, dysregulation of autophagy has been implicated in multiple neurodegenerative disorders. Previous studies reported that autophagy affects the processing of amyloid precursor protein (APP), thus stimulating β‐amyloid (Aβ) production in Alzheimer’s disease (AD) eventually. Although the mechanism of autophagy modulation on APP processing and its pathogenesis has not yet been fully elucidated at the molecular level, but modulation of autophagy has received considerable attention as a promising approach for the treatment of AD. In the early stage of AD, Aβ may prompt autophagy to facilitate its removal via mTOR‐independent as well as-dependent pathways. However, a recent study proposed that autophagy processes are not properly regulated as AD continues to progress, and consequently, the production of Aβ tends to accumulate rapidly. Meanwhile, a number of autophagy-related genes (Atg) as well as APP genes are also thought to influence the development of AD, which may serve as a bi‐directional link to autophagy and AD pathology. In this review, we summarized current observations related to autophagy regulation and APP processing, focusing on their dynamic modifications associated with the progression of AD. Recent findings together highlight the essential role of autophagy in the removal and clearance of APP and Aβ deposition in the pathological condition of AD.
ARTICLE | doi:10.20944/preprints202306.0617.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Brain-derived neurotrophic factor; nerve growth factor; Alzheimer’s disease; allosteric modulator; cognitive function; anti-depressant
Online: 8 June 2023 (09:55:01 CEST)
The introduction of anti-amyloid monoclonal antibodies against Alzheimer’s disease (AD) is of high importance. However, even though treated patients show very little amyloid pathology, there is only a modest effect on the rate of cognitive decline. Although this effect possibly can increase over time, there is still a need for alternative treatments that will improve the cognitive function in patients with AD. Therefore, the purpose of this study was to characterize the triazinetrione ACD856, a novel pan-Trk positive allosteric modulator, in multiple models to address its neuroprotective and potential disease modifying effects. The pharmacological effect of ACD856 was tested in recombinant cell lines, primary cortical neurons or animals. We demonstrate that ACD856 enhanced NGF-induced neurite outgrowth, increased the levels of the pre-synaptic protein SNAP25 in PC12 cells and increased the degree of phosphorylated TrkB in SH-SY5Y cells. In primary cortical neurons, ACD856 led to increased levels of phospho-ERK1/2, showed neuroprotective effect against amyloid-beta or energy-deprivation induced neurotoxicity, and increased the levels of brain derived neurotrophic factor (BDNF). Consequently, administration of ACD856 resulted in a significant increase of BDNF in the brains of 21-months old mice. Furthermore, repeated administration of ACD856 resulted in a sustained anti-depressant effect which lasted up to seven days, suggesting effects that go beyond merely symptomatic effects. In conclusion, the results confirm ACD856 as a cognitive enhancer, but more importantly, they provide substantial in vitro and in vivo evidence of neuroprotective and long-term effects that contribute to neurotrophic support and increased neuroplasticity. Presumably, the described effects of ACD856 may improve cognition, increase resilience, and promote neurorestorative processes, thereby leading to a healthier brain in patients with AD.
ARTICLE | doi:10.20944/preprints202308.1583.v1
Subject: Biology And Life Sciences, Aging Keywords: Telomere length; Telomeres; Alzheimer’s Disease; late-onset AD, Aging, Neurodegeneration
Online: 22 August 2023 (13:22:03 CEST)
Telomeres are structures at the ends of eukaryotic chromosomes that help maintain genomic stability. During aging, telomere length gradually shortens, producing short telomeres, which are considered markers of premature cellular senescence. This is believed to contribute to age-related diseases, including Alzheimer's disease (AD) and based on this, several studies have hypothesized that telomere shortening may characterize AD. Current research, however, has been inconclusive regarding the direction of the association between leukocyte telomere length (LTL) and disease risk. We assessed the association between LTL and AD in a retrospective case-control study of a sample of 255 unrelated patients with late-onset AD (LOAD), including 120 sporadic cases and 135 with positive family history for LOAD, and a group of 279 cognitively healthy unrelated controls, which were all from Calabria, a region from south Italy. Following regression analysis, telomeres were found to be significantly shorter in LOAD cases than in controls (p<0.001 for both sporadic and familial cases). Interestingly, LTL were associated to disease risk independently of the presence of conventional risk factors (e.g., age, sex, MMSE scores, presence of the APOE-ε4 allele). Altogether, our findings lend support to the notion that LTL shortening may be an indicator of the patho-genesis of LOAD.
ARTICLE | doi:10.20944/preprints202311.0513.v1
Subject: Engineering, Bioengineering Keywords: Alzheimer’s disease (AD); Mild Cognitive Impairment (MCI); FDG PET; Radiomics
Online: 8 November 2023 (15:54:44 CET)
Abstract: This study presents a methodological framework for AD and MCI diagnosis using radiomic analysis of 18FDG-PET imaging and conducts non-invasive predictions and in-depth analysis of AD and MCI and the associated small number of regions and features. Our methodology follows a structured process commencing with data preprocessing and labeling, facilitating segmentation through FastSurfer, a tool that efficiently segments the brain into 95 ROIs using the DKT-atlas. Subsequently, Feature extraction was carried out using PyRadiomics, calculating 120 features for each of the 95 ROIs (11,400 per image). These extracted features form the foundation of our radiomics analysis, primarily for early diagnostic purposes. In the feature selection phase, we explored a set of eight commonly employed techniques, including ANOVA, PCA, and LASSO, originating from the four main categories, namely filtered, embedded, wrapper, and hybrid methods, to identify a pertinent subset of features. Our evaluation assessed the performance of nine classification methods, such as GradientBoosting, RandomForest, and GaussianNB, in conjunction with eight feature selection techniques. The choice of feature selection method and classifiers was predicated on their ability to achieve the best area under the ROC curve with independent data. For all three predictions AD vs. CN, AD vs. MCI, and CN vs. MCI the Random Forest (RF) classifier with LASSO feature selection demonstrated the highest accuracy with an AUC of 0.976 for AD vs CN, AUC=0.917 for AD vs MCI, and AUC=0.877 for MCI vs CN. In conclusion, our RAB-PET platform enables efficient AD and MCI diagnosis from FDG-PET images using a radiomics pipeline. It also offers a general hardware and software tool for the investigation of other brain disorders.
ARTICLE | doi:10.20944/preprints201907.0345.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s Disease; Extreme Gradient Boosting; Deep Residual Learning; conolutional neural networks; machine learning; dementia
Online: 31 July 2019 (04:33:43 CEST)
Alzheimer's is a disease for which there is no cure. Diagnosing Alzheimer's Disease (AD) early facilitates family planning and cost control. The purpose of this study is to predict the presence of AD using socio-demographic, clinical, and Magnetic Resonance Imaging (MRI) data. Early detection of AD enables family planning and may reduce costs by delaying long-term care. Accurate, non-imagery methods also reduce patient costs. The Open Access Series of Imaging Studies (OASIS-1) cross-sectional MRI data were analyzed. A gradient boosted machine (GBM) predicted the presence of AD as a function of gender, age, education, socioeconomic status (SES), and Mini-Mental State Exam (MMSE). A Residual Network with 50 layers (ResNet-50) predicted CDR presence and severity from MRI's (multi-class classification). The GBM achieved a mean 91.3% prediction accuracy (10-fold stratified cross validation) for dichotomous CDR using socio-demographic and MMSE variables. MMSE was the most important feature. ResNet-50 using image generation techniques based on an 80% training set resulted in 98.99% three class prediction accuracy on 4,139 images (20% validation set) at Epoch 133 and nearly perfect multi-class predication accuracy on the training set (99.34%). Machine Learning methods classify AD with high accuracy. GBM models may help provide initial detection based on non-imagery analysis, while ResNet-50 network models might help identify AD patients automatically prior to provider review.
ARTICLE | doi:10.20944/preprints202001.0109.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Alzheimer’s disease; curcumin; network pharmacology; molecular simulation; neurodegeneration; TrkB/PI3K signaling; autophagy
Online: 11 January 2020 (13:53:12 CET)
Curcumin is one of the bioactive metabolites of turmeric (Curcuma longa), known for its pleiotropic pharmacological actions, including antioxidant and anti-inflammation, anticholinesterase, immunomodulation, and neuroprotection. Substantial evidence suggests the therapeutic benefits of curcumin against neurodegenerative disorders, including Alzheimer’s disease (AD), acting on a diverse array of brain targets that make the molecular mechanisms complicated. System biology level-investigation could potentially present a comprehensive molecular mechanism to delineate the neuropharmacological action of curcumin. In this study, we used integrated system pharmacology and molecular simulation analysis to gain insights into the underlying mechanism of curcumin action against AD. Network pharmacology study identified curcumin-targeted potential cellular pathways such as phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling, neurotrophin signaling, toll-like receptor (TLR) signaling, and autophagy, and proteins such as tropomyosin receptor kinase B (TrkB), liver X-receptor-beta (LXR-β), estrogen receptor-β (ER-β), mammalian target of rapamycin (mTOR), TLR-2, N-methyl-D-acetate receptor subunit 2B (GluN2B), β-secretase and glycogen synthase kinase-3β (GSK-3β), which are intimately associated with neuronal growth and survival, immune response, and inflammation. Moreover, the molecular modeling further verified that curcumin showed a significant binding affinity to mTOR, TrkB, LXR-β, TLR-2, ER-β, GluN2B, β-secretase, and GSK-3β, which are the crucial regulators of molecular and cellular processes associated with AD. Together, the present system pharmacology and in silico findings demonstrate that curcumin might play a significant role in modulating AD-pathobiology, supporting its therapeutic application for the prevention and treatment of AD.
REVIEW | doi:10.20944/preprints201806.0407.v2
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: glial cells; astrocytes; NG2 glia; microglia; oligodendrocytes; Alzheimer’s disease; neurodegenerative disease; Aβ-peptides
Online: 14 September 2018 (03:13:57 CEST)
Even though Alzheimer’s disease (AD) is of significant interest to the scientific community, its pathogenesis is very complicated and not well-understood. A great deal of progress has been made in AD research recently and with the advent of these new insights more therapeutic benefits may be identified that could help patients around the world. Much of the research in AD thus far has been very neuron-oriented; however, recent studies suggest that glial cells, i.e., microglia, astrocytes, oligodendrocytes, and oligodendrocyte progenitor cells (NG2 glia), are linked to the pathogenesis of AD and may offer several potential therapeutic targets against AD. In addition to a number of other functions, glial cells are responsible for maintaining homeostasis (i.e., concentration of ions, neurotransmitters, etc.) within the central nervous system (CNS) and are crucial to the structural integrity of neurons. This review explores the: (i) role of glial cells in AD pathogenesis; (ii) complex functionalities of the components involved; and (iii) potential therapeutic targets that could eventually lead to a better quality of life for AD patients
ARTICLE | doi:10.20944/preprints202307.0732.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: Alzheimer’s disease; diltiazem; intra-cerebroventricular; streptozotocin; cognition; amyloid beta; anti-oxidant enzymes
Online: 11 July 2023 (12:29:33 CEST)
Alzheimer’s disease (AD) is an age-related neuropsychiatric disorder and a common cause of progressive dementia. Diltiazem (DTZ), the non-dihydropyridine benzothiazepine class of calcium channel blocker (CCB), used clinically in angina and other cardiovascular disorders have proven neurological benefits. In the present study, the neuroprotective anti-dementia effects of DTZ against intra-cerebroventricular-streptozotocin (ICV-STZ)-induced sporadic AD (SAD)-type rat model was investigated. ICV-STZ-induced cognitive impairments were measured by passive avoidance and Morris water maze tasks. Anti-oxidative enzyme status, pro-inflammatory markers, and amyloid-beta (Aβ) protein expression in rat brain tissues were measured by ELISA kits, Western blotting, and immunostaining techniques. Data revealed that ICV-STZ injection in rats significantly induced cognitive deficits and altered the levels of oxidative and pro-inflammatory markers (p < 0.05 ~ p < 0.001). Treatment with DTZ (10 mg/kg, 20 mg/kg, and 40 mg/kg. p.o.) daily for twenty-one days, 1 h before a single ICV-STZ (3 mg/kg) injection, significantly improved cognitive impairments, ameliorated the ICV-STZ-induced altered nitrite, pro-inflammatory cytokines (TNF-α, and IL-1β) and anti-oxidative enzyme levels (superoxide dismutase, lipid peroxidation, and glutathione). Further, DTZ restored the increased Aβ protein expression in ICV-STZ-induced brain tissue Considering the data obtained, DTZ exhibited a potential neuroprotective anti-dementia role in ICV-STZ-induced SAD-type conditions in rats and might be repurposed as a potential therapeutic agent in the treatment and management of AD and related dementia pathologies.
REVIEW | doi:10.20944/preprints201807.0481.v2
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: protein tau; Alzheimer’s disease; neurodegenerative disease; synaptic dysfunction; Aβ-peptides; tau-imaging
Online: 27 August 2018 (11:25:45 CEST)
One of the most commonly known chronic neurodegenerative disorders, Alzheimer’s disease (AD), manifests the common type of dementia in 60–80% of cases. From a clinical standpoint, a patent cognitive decline and a severe change in personality, as caused by a loss of neurons, is~usually evident in AD with about 50 million people affected in 2016. The disease progression in patients is distinguished by a gradual plummet in cognitive functions, eliciting symptoms such as memory loss, and eventually requiring full-time medical care. From a histopathological standpoint, the~defining characteristics are intracellular aggregations of hyper-phosphorylated tau protein, known as neurofibrillary tangles (NFT), and depositions of amyloid β-peptides (Aβ) in the brain. The~abnormal phosphorylation of tau protein is attributed to a wide gamut of neurological disorders known as tauopathies. In addition to the hyperphosphorylated tau lesions, neuroinflammatory processes could occur in a sustained manner through astro-glial activation, resulting in the disease progression. Recent findings have suggested a strong interplay between the mechanism of Tau phosphorylation, disruption of microtubules, and synaptic loss and pathology of AD. The mechanisms underlying these interactions along with their respective consequences in Tau pathology are still ill-defined. Thus, in this review: (1) we highlight the interplays existing between Tau pathology and AD; and (2) take a closer look into its role while identifying some promising therapeutic advances including state of the art imaging~techniques.
ARTICLE | doi:10.20944/preprints201808.0371.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s disease; central nervous system; hypertension; brain-derived neurotrophy factor; NADPH oxidase
Online: 21 August 2018 (06:04:03 CEST)
Recent studies have indicated that several anti-hypertensive drugs may delay the development and progression of Alzheimer’s disease (AD). However, the relationships among AD, hypertension, and oxidative stress remain to be elucidated. In the present study, we aimed to determine whether treatment with resveratrol reduces reactive oxygen species (ROS) generation in the brain, thereby reducing cognitive impairment in rats with angiotensin II (Ang-II)-induced early AD. Male WKY rats with Ang-II-induced AD were treated with losartan or resveratrol for 2 weeks. Our results revealed that treatment with resveratrol (10 mg/kg/day) decreased blood pressure, increased levels of brain-derived neurotrophic factor (BDNF) in the hippocampus, and decreased ROS production in the nucleus tractus solitarius (NTS) in the Ang-II groups. In addition, inhibition of TauT231 phosphorylation in the hippocampus using resveratrol significantly abolished Ang-II-induced expression of Ab precursors, active caspase 3, and glycogen synthase kinase 3b (GSK-3b)Y216 while increasing AktS473 phosphorylation. Notably, resveratrol reversed impairments in hippocampal-dependent contextual memory induced by deleting NADPH oxidase and NOX2. Overall, our results suggest that resveratrol exerts neuroprotective effects against memory impairment and hippocampal damage in a rat model of early stage AD by reducing oxidative stress. These novel findings indicate that resveratrol may represent a pharmacological option for patients with hypertension at a risk of AD during old age.
REVIEW | doi:10.20944/preprints202201.0098.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: BPSD; Alzheimer’s dementia; agitation; psychosis; SSRIs; antipsychotics; brexpiprazole; dextromethorphan
Online: 10 January 2022 (11:12:38 CET)
Background: The psychomotor agitation of the BPSD is one of the common issues in aged care facilities, leading to the poor functional and medical consequences. Psychotropic interventions are the preferable choice of treatment. But which medication should be the prescribers first preference? This review aims to compare pharmacological interventions for psychomotor agitation, judging them according to their effectuality and justifiability profiles. This is to be achieved by retrieving information from RCTs and systematic reviews. Objectives: This review evaluates evidence from RCTs, systematic reviews, and meta-analyses of BPSD patients who had taken agitation treatments. Assessing the efficacy of antidepressants and antipsychotic treatments when compared to each other for the purpose of improving agitation outcomes. Methods: This narrative review includes RCTs and retrospective studies that were comparing one or more active ingredient medications with another or with a placebo, along with sys-tematic reviews comparing antidepressants with antipsychotics such as quetiapine, olanzapine, and risperidone. Studies extracted by searching accessing databases, such as PubMed, OVID, and Cochrane with restrictions of date from 2000 to 2021 and English language. Quality of evidence: The quality of systematic reviews was judged against AMSTAR score, and RCTs were judged according to CONSORT checklist for RCT protocols. Conclusion: There are still few studies of serotonin targeting treatment of agitation in BPSD. The SSRIs such as citalopram were associated with a reduction in symptoms of agitation, and lower risk of adverse effects compared to antipsychotics. This review also illustrates brexpiprazole as a target of multimodal neurotransmitters such as dopamine, serotonin, and norepinephrine; and dextromethorphan, OR dextromethorphan associated with bupropion or quinidine as a blockade of NMDA receptors. The outcome of this review suggests that further studies involving more dementia/Alzheimer’s participants should be conducted. Future studies are required also to assess the long-term safety and efficacy of SSRI, brexpiprazole, dextromethorphan treatments for agitation in BPSD.
ARTICLE | doi:10.20944/preprints202304.1128.v1
Subject: Biology And Life Sciences, Aging Keywords: APOE locus; TOMM40; APOE; oxidative stress; mitochondrial dysfunction; mitochondrial DNA copy number; gene expression; Alzheimer’s disease; aging
Online: 28 April 2023 (07:08:33 CEST)
The APOE locus has garnered significant clinical interest because of its association with Alzheimer's disease (AD) and longevity. This genetic association appears across multiple genes in the APOE locus. Despite the apparent differences between AD and longevity, both conditions share a commonality of aging-related changes in mitochondrial function. This commonality is likely due to accumulative biological effects, partly exerted by the APOE locus. In this study, we investigated changes in mitochondrial structure/function-related markers using oxidative stress-induced human cellular models and postmortem brains (PMBs) from individuals with AD and normal controls. Our results reveal a range of expressional alterations, either up- or down-regulated, in these genes in response to oxidative stress. In contrast, we consistently observed an upregulation of multiple APOE locus genes in all cellular models and AD PMBs. Additionally, the effects of AD status on mitochondrial DNA copy number (mtDNA CN) varied depending on APOE genotype. Our findings imply a potential coregulation of APOE locus genes, possibly occurring within the same topologically associating domain (TAD) of the 3D chromosome conformation. The coordinated expression of APOE locus genes could impact mitochondrial function, contributing to the development of AD or longevity. Our study underscores the significant role of the APOE locus in modulating mitochondrial function and provides valuable insights into the underlying mechanisms of AD and aging, emphasizing the importance of this locus in clinical research.
ARTICLE | doi:10.20944/preprints202105.0267.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s disease; AD; blood-based biomarker; p53; unfolded p53; U-p53
Online: 12 May 2021 (11:21:18 CEST)
Background: Research continues to search for blood-based biomarkers sensitive to Alzheimer’s disease (AD) pathology during the initial stages when symptoms of cognitive decline are not yet apparent. A blood-based biomarker candidate is metalloprotein p53, the conformation of which was previously found to be altered in peripheral cells from individuals with mild cognitive impairment (MCI) and AD, presenting as an unfolded p53 (U-p53) conformational variant. Methods: Plasma samples from the well-characterized Australian Imaging, Biomarkers, and Lifestyle (AIBL) cohort were used to identify the clinically relevant AZ 284® peptide, specifically present in samples from individuals with symptomatic AD. The AZ 284® peptide, which is a marker of the U-p53 conformational variant (U-p53AZ), was identified by immunoprecipitation (IP) with a novel U-p53 conformational variant-specific antibody followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS) and protein sequencing. Using IP-LC surface-activated chemical ionization (SACI) MS/MS analysis, the prognostic and diagnostic performance of U-p53AZ were examined in the longitudinal AIBL cohort, including 252 plasma samples derived from 214 elderly individuals. For the prognostic analyses, U-p53AZ levels were assessed at 36, 72, and 90 months after baseline assessment. Results: The prognostic performance of U-p53AZ to predict the progression to AD from preclinical or prodromal AD was high, with area under the receiver operating characteristic curve (AUC) values close to or above 0.90. Furthermore, U-p53AZ predicted the progression to AD more than 6 years prior to symptom onset with positive and negative predictive values of about 90%. Additionally, the estimated prognostic performance of U-p53AZ was superior to other main risk factors (i.e., age, sex, and either alone or in combination with amyloid status. Furthermore, U-p53AZ had high diagnostic performance to differentiate cognitively normal individuals from those with AD (AUC values >0.88). Conclusion: These findings support the use of U-p53AZ as a prognostic blood-based biomarker accurately predicting the progression to AD dementia during the preclinical and prodromal stages at least 6 years before receiving the clinical diagnosis of AD dementia.
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: paraoxonases; oxidative stress; Alzheimer’s disease; brain; Tg2576 mice; astrocytes; hippocampus; amyloid-β; microglia; neurons
Online: 18 December 2020 (11:53:45 CET)
Background: Brain oxidative lipid damage and inflammation are common in neurodegenerative diseases such as Alzheimer’s disease (AD). Paraoxonase-1 and 3 (PON1 and PON3) protein expression have been described in tissues with no PON1 and PON3 gene expression. In the present study, we aimed to examine differences in PON1 and PON3 protein expression in the brain of a mouse model of AD. Methods: We used peroxidase-based and fluorescence-based immunohistochemistry in 5 brain regions (olfactory bulb, forebrain, posterior midbrain, hindbrain and cerebellum) of transgenic (Tg2576) mice with the Swedish mutation (KM670/671NL) responsible for a familial form of AD and corresponding wild-type mice. Results: We found intense PON1 and PON3 positive staining in star-shaped cells surrounding Aβ plaques in all Tg2576 mouse brain regions studied. Although we could not co-localize PON1 and PON3 with astrocytes, brain star-shaped cells, we found some co-localization of PON3 with microglia. Conclusions: These results suggest that 1) PON1 and PON3 cross the blood-brain barrier in discoidal HDLs and are transferred to specific brain cell types, and 2) PON1 and PON3 play an important role in preventing oxidative stress and lipid peroxidation in particular cell types, likely astrocytes and microglia, in AD pathology, and potentially in other neurodegenerative diseases
ARTICLE | doi:10.20944/preprints202305.1784.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s disease; cerebrospinal fluid; inflammasome; microglia; mild cognitive impairment; plasma; tau protein; TREM2
Online: 25 May 2023 (09:40:33 CEST)
People with specific TREM2 gene variants are more prone to develop Alzheimer's disease (AD). The TREM2 receptor regulates the number of myeloid cells, phagocytosis, and the inflammatory response via interacting with apolipoproteins and amyloid. Higher TREM2 expression has been found to protect against AD. When TREM2 activity increases, the activity of genes involved in the activation of microglia cells decreases. This can improve the efficiency of phagocytosis. When TREM2 is highly expressed and the inflammasome is activated, the results are not always congruent. Therefore, this study aimed to discover how sTREM2 levels in CSF and plasma samples relate to other indices of AD pathology. We examined 98 AD plasma samples, 35 plasma samples of subjects with mild cognitive impairment (MCI), 11 healthy controls (HC) plasma samples, as well as 155 AD CSF samples, 90 MCI CSF samples, and 50 HC CSF samples. CSF sTREM2 levels were higher in the AD group than in the MCI and HC groups, in contrast to plasma sTREM2. This shows that CSF sTREM2 levels could be used to distinguish between healthy and AD patients. CSF sTREM2 levels were significantly correlated with neurofibrillary changes, cognitive decline, and inflammasome activity in AD patients. While our findings are consistent with previous research, future studies will need to include more patients and employ standardized methodological approaches to add CSF sTREM2 to the list of biomarkers for AD.
REVIEW | doi:10.20944/preprints202306.1273.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: neurodegenerative diseases; Alzheimer’s disease; natural compounds; RNA therapy; blood-brain barrier; exosome-like liposomes
Online: 19 June 2023 (03:33:29 CEST)
With the increment of the aging population in recent years, neurodegenerative diseases exert a major global disease burden, essentially as a result of the lack of treatments that can stop the disease progression. Alzheimer’s Disease (AD) is an example of a neurodegenerative disease, that affects millions of people globally, with no effective treatment. Natural compounds have emerged as a viable therapy to fill a huge gap in AD management, and in recent years, mostly fuelled by the Covid-19 pandemic, RNA-based therapeutics have become a hot topic in the treatment of several diseases. Treatments of neurodegenerative diseases face significant limitations due to the complex and interconnected pathways that lead to their hallmarks and, also due to the necessity to cross the blood–brain barrier. Nanotechnology has contributed to surpass this bottleneck in the treatment of AD, by promoting safe and enhanced drug delivery to the brain. In particular, exosome-like nanoparticles, a hybrid delivery system combining exosomes and liposomes' advantageous features, are demonstrating great potential in the treatment of central nervous system diseases.
ARTICLE | doi:10.20944/preprints202305.0982.v1
Subject: Computer Science And Mathematics, Artificial Intelligence And Machine Learning Keywords: Alzheimer’s Disease; SH-SY5Y cells; Nuclear Magnetic Resonance (NMR); Convolutional autoencoders; Embedding of NMR spectra; Data augmentation.
Online: 15 May 2023 (05:42:08 CEST)
Alzheimer’s Disease (AD) affects the quality of life of millions of people worldwide and represents one of the biggest challenges for the whole society. The SH-SY5Y neuroblastoma cell line is often used as an in vitro model of neuronal function and is widely applied to study the molecular events leading to AD. In the last few years, basic research on SH-SY5Y cells has provided interesting insights for the discovery of new drugs and biomarkers for improved AD treatment and diagnosis. At the same time, untargeted NMR metabolomics is widely applied on biological fluids for (i) metabolic profile analysis, (ii) screening for differential metabolites, (iii) analysis of metabolic pathways, and (iv) the discovery of new biomarkers. Principal Component Analysis (PCA) and Linear Discriminant Analysis (LDA) have proved to be powerful methods for processing NMR data, being useful in signal quantization, even if more sophisticated --- typically non--linear --- techniques are needed to obtain compact yet information--rich embeddings for complex spectra. In this paper, a compression technique based on convolutional autoencoders is proposed, which can perform a high dimensionality reduction of the spectral signal (up to more than 300 times), maintaining informative features (guaranteed by a reconstruction error always smaller than 5%). Moreover, before compression, an ad hoc preprocessing method was devised to remedy the scarcity of available data. The compressed spectral data were then used to train some SVM classifiers to distinguish diseased from healthy cells, achieving an accuracy close to 78%, a significantly better performance with respect to using PCA--compressed data.
REVIEW | doi:10.20944/preprints202108.0237.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Alzheimer’s disease; cytokines; chemokines; neuroinflammation; neurotrophic factors; pathophysiology; Blood brain barrier; mild cognitive impairment; brain health; therapeutics
Online: 10 August 2021 (15:49:12 CEST)
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized mainly by the gradual decay in neuronal function as a consequence of diverse degenerating events primarily including mitochondria dysfunction and cascades of neuro-immune reactions. Besides the acquired harmful reactive oxygen species (ROS), neurotoxins, and amyloid-beta (Aβ) and TAU pathologies in neurons, accumulating evidence with time underlined the roles of cytokines and growth factors in the AD pathogenesis. It may help us in evaluating the propensities and specific mechanism(s) of cytokines and factors impacting neuron upon apoptotic decline. Proinflammatory cytokines often induce inflammation in AD and AD-like pathogenesis in response to the apoptotic scenarios where some growth factors are involved in cytokinetic reactions to activate microglia and causing inflammation in AD. In this report, we comprehensively reviewed role of cytokines and chemokines in immune response to AD and neuropsychiatry. We provided insights into the neuroinflammation and the role of diverse factors including the pro-/anti-inflammatory cytokines, APP, TAU phosphorylation, glycation end products, complement system, and the role of glial cells. Also, we discussed the pathogenic and protective role of macrophage migration inhibitory factors, choroid plexus-, neurotrophic- and hematopoietic -related growth factors in AD. We further shed light on the availability and accessibility of the cytokines across the blood-brain barrier in AD pathophysiology. Taken together, the emerging role of these factors in AD pathology emphasized the importance of building novel strategies for an effective therapeutic/neuropsychiatric management of AD in clinics.
ARTICLE | doi:10.20944/preprints202104.0532.v3
Subject: Social Sciences, Psychology Keywords: Locus Coeruleus; Reserve; Brain Age; Visual Attention; Alzheimer’s Disease; Mild Cognitive Impairment; normal Aging; Neuroimaging; Voxel Based Morphometry
Online: 21 June 2021 (11:41:40 CEST)
The noradrenergic theory of Cognitive Reserve (Robertson, 2013-2014) postulates that the upregulation of the Locus Coeruleus - Noradrenergic System (LC-NA) originating in the Brainstem might facilitate cortical networks involved in attention, and protracted activation of this system throughout the lifespan may enhance cognitive stimulation contributing to Reserve. To test the above-mentioned theory, a study was conducted on a sample of 686 participants (395 controls, 156 Mild Cognitive Impairment, 135 Alzheimer’s Disease) investigating the relationship between LC volume, attentional performance and a biological index of brain maintenance (BrainPAD – an objective measure which compares an individual’s structural brain health, reflected by their voxel-wise grey matter density, to the state typically expected at that individual’s age). Further analyses were carried out on Reserve indices including education and occupational attainment. Volumetric variation across groups was also explored along with gender differences. Control analyses on the Serotoninergic (5-HT), Dopaminergic (DA) and Cholinergic (Ach) systems were contrasted with the Noradrenergic (NA) hypothesis. The antithetic relationships were also tested across the neuromodulatory subcortical systems.Results supported by bayesian modelling showed that LC volume disproportionately predicted higher attentional performance as well as biological brain maintenance across the three groups. These findings lend support to the role of the noradrenergic system as a key mediator underpinning the neuropsychology of Reserve, and they suggest that early prevention strategies focused on the noradrenergic system (e.g. cognitive-attentive training, physical exercise, pharmacological and dietary interventions) may yield important clinical benefits to mitigate cognitive impairment with age and disease.
REVIEW | doi:10.20944/preprints202301.0239.v1
Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: Alzheimer’s disease; Nerve growth factor receptor; NGFR; p75NTR; amyloid-beta; expression; signaling pathways; neuropathology; diagnosis; treatment.
Online: 13 January 2023 (07:37:10 CET)
Alzheimer’s disease (AD) represents the most prevalent type of dementia in elderly people, primarily characterized by brain accumulation of beta-amyloid (Aβ) peptides, derived from Amyloid Precursor Protein (APP), in the extracellular space (amyloid plaques) and intracellular deposits of the hyperphosphorylated form of the protein tau (p-tau; tangles or neurofibrillary aggregates). The Nerve growth factor receptor (NGFR/p75NTR) represents a low-affinity receptor for all known mammalians neurotrophins (i.e., pro-NGF, NGF, BDNF, NT-3 e NT-4/5) and it is involved in pathways that determine both survival and death of neurons. Interestingly, also Aβ peptides can blind to NGFR/p75NTR making it the “ideal” candidate in mediating Aβ-induced neuropathology. Besides pathogenesis and neuropathology, several data indicated that NGFR/p75NTR could play a key role in AD also from a genetic perspective. Other studies suggested that NGFR/p75NTR could represent a good diagnostic tool, as well as a promising therapeutic target for AD. Here, we comprehensively summarize and review the current experimental evidence on this topic.
REVIEW | doi:10.20944/preprints202101.0625.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s disease; dementia, beta-amyloid; germ theory; drug development; clinical trials; herpes; spirochetes; Chlamydia pneumoniae; Porphyromonas gingivalis; toxoplasma; mycobacteria
Online: 29 January 2021 (13:57:18 CET)
There is now considerable evidence that several infectious agents (viruses, bacteria, or parasites) may play a contributing role in the development of Alzheimer’s disease (AD). The six primary suspects are herpes viruses, spirochetal bacteria, Chlamydia pneumoniae, Porphyromonas gingivalis, mycobacteria, and toxoplasma parasites. Also, some of the antimicrobial and antiviral agents that are used to treat them have shown promise for AD interventions. I describe this evidence and assert it is now time to accelerate clinical trials of these existing drugs, already federally approved, to determine if such treatments can delay, halt, or reverse AD.
ARTICLE | doi:10.20944/preprints202003.0297.v1
Subject: Computer Science And Mathematics, Information Systems Keywords: Data Mining; Alzheimer’s Dementia; Composite Hybrid Feature Selection; Machine learning; Stack Hybrid Classification; AI Techniques; Classification; AD Diagnose; Clinical AD Dataset
Online: 19 March 2020 (10:52:31 CET)
Alzheimer's disease (AD) is a significant regular type of dementia that causes damage in brain cells. Early detection of AD acting as an essential role in global health care due to misdiagnosis and sharing many clinical sets with other types of dementia, and costly monitoring the progression of the disease over time by magnetic reasoning imaging (MRI) with consideration of human error in manual reading. Our proposed model, in the first stage, apply the medical dataset to a composite hybrid feature selection (CHFS) to extract new features for select the best features to improve the performance of the classification process due to eliminating obscures features. In the second stage, we applied a dataset to a stacked hybrid classification system to combine Jrip and random forest classifiers with six model evaluations as meta-classifier individually to improve the prediction of clinical diagnosis. All experiments conducted on a laptop with an Intel Core i7- 8750H CPU at 2.2 GHz and 16 G of ram running on windows 10 (64 bits). The dataset evaluated using an explorer set of weka data mining software for the analysis purpose. The experimental show that the proposed model of (CHFS) feature extraction performs better than principal component analysis (PCA), and lead to effectively reduced the false-negative rate with a relatively high overall accuracy with support vector machine (SVM) as meta-classifier of 96.50% compared to 68.83% which is considerably better than the previous state-of-the-art result. The receiver operating characteristic (ROC) curve was equal to 95.5%. Also, the experiment on MRI images Kaggle dataset of CNN classification process with 80.21% accuracy result. The results of the proposed model show an accurate classify Alzheimer's clinical samples against MRI neuroimaging for diagnoses AD at a low cost.
REVIEW | doi:10.20944/preprints202205.0166.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Antimicrobial Peptides (AMPs); Alzheimer’s Disease (AD); infectious hypothesis; beta-amyloid (Ab); lactoferrin; defensins; cystatins; thymosin β4; histatin 1; statherin
Online: 12 May 2022 (09:40:33 CEST)
Alzheimer's Disease (AD) represents the most frequent type of dementia in elderly people. There are two major forms of the disease: sporadic (SAD) - whose causes are not completely understood - and familial (FAD) - with clear autosomal dominant inheritance. The two main hallmarks of AD are extracellular deposits of amyloid-beta (Ab) peptide and intracellular deposits of the hyperphosphorylated form of the tau protein (P-tau). An ever-growing body of research supports the infectious hypothesis of sporadic forms of AD. Indeed, it has been documented that some pathogens, such as herpesviruses and certain bacterial species, are commonly present in AD patients, prompting recent clinical research to focus on the characterization of Antimicrobial Peptides (AMPs) in this pathology. Literature also demonstrates that Ab can be considered itself as an AMP thus representing a type of innate immune defense peptide that protect the host against a variety of pathogens. Beyond Ab, other proteins with antimicrobial activity, such as lactoferrin, defensins, cystatins, thymosin β4, LL37, histatin 1 and statherin have been shown to be involved in AD. Here we have summarized and discussed these findings and explored the diagnostic and therapeutic potential of AMPs in AD.
REVIEW | doi:10.20944/preprints202309.0210.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: Brain-derived neurotrophic factor (BDNF); Alzheimer’s disease; exercise; osteocalcin; FNDC5/irisin; lactate; APP processing; dementia; cognition; learning and memory
Online: 5 September 2023 (03:45:49 CEST)
Brain-derived neurotrophic factor (BDNF) is a key molecule in promoting neurogenesis, dendritic and synaptic health, and neuronal survival, plasticity, and excitability, all of which are disrupted in neurological and cognitive disorders such as Alzheimer’s disease (AD). Extracellular aggregates of amyloid-β (Aβ) in the form of plaques and intracellular aggregates of hyperphosphorylated tau protein have been identified as major pathological insults in AD brain, along with immune dysfunction, oxidative stress, and other toxic stressors. Although aggregated Aβ and tau lead to decreased brain BDNF expression, early losses in BDNF prior to plaque and tangle formation may be due to other insults such as oxidative stress and contribute to early synaptic dysfunction. Physical exercise, on the other hand, protects synaptic and neuronal structure and function, with increased BDNF as a major mediator of exercise-induced enhancements in cognitive function. Here, we review recent literature on mechanisms behind exercise induced BDNF upregulation and its effects on improving learning and memory and on Alzheimer’s disease pathology. Mechanisms include elevations in peripheral BDNF-inducing hormones such as osteocalcin, FNDC5/irisin, and lactate. The fundamental mechanisms of how exercise impacts BDNF and cognition are unclear but are a prerequisite to developing new biomarkers and therapies to delay or prevent cognitive decline.
REVIEW | doi:10.20944/preprints202302.0173.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: ifampin; proteinopathies; permeability glycoprotein; intranasal; bi-directional; Alzheimer’s; Parkinson’s; Lewy body dementia; multiple system atrophy; huntington’s; amyotrophic lateral sclerosis/frontotemporal dementia spectrum
Online: 10 February 2023 (02:31:56 CET)
This article proposes the use of intranasal rifampin as a means to improve protein homeostasis and disaggregate misfolded proteins in the age-related neurodegenerative proteinopathies. Alzheimer’s disease, Parkinson’s disease, multi-system atrophy, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis and Huntington’s disease are all, at the core, proteinopathies. Although these diseases varying greatly in the specific disease-associated proteins, anatomic sites of the abnormal protein deposition and clinical presentations, what they have in common is disruption of normal “housekeeping” functions related to protein homeostasis, proteostasis. The prospect of pharmacologically augmenting autophagic capacity with a known drug repurposed to improve proteostasis is attractive; to accomplish these ends with an inexpensive drug with relative ease of delivery adds to the attractiveness. Rifampin can be delivered to the brain via the intranasal route. Rifampin has been used for decades primarily against mycobacterial infection; it has been given with intravenous, oral, intrathecal and topical routes including as eyedrops and nasal spray. Rifampin disaggregates toxic oligomers in vitro; given intranasally, rifampin improves memory and clears pathologic proteins in animal models of the proteinopathies. Rifampin acts as both a gatekeeper and a housekeeper against the abnormal proteins of these diseases. This article suggests the merit of a clinical trial with intranasal rifampin to boost protein homeostasis in the most common age-related neurodegenerative proteinopathy, Alzheimer’s disease. The primary outcome of such a trial is change in risk of Alzheimer’s pathology as measured by plasma-based amyloid peptide 42/40 testing pretreatment and follow-up testing after 6 months of intranasal rifampin.
REVIEW | doi:10.20944/preprints202305.1229.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Molecular Genetics; Neurodegenerative Disease; Molecular pathology; Epigenetics; Gene expression; Therapeutic targets; Biomarkers; Alzheimer’s Disease; Parkinson’s Disease; Huntington Disease; Amyotrphic Lateral Sclerosis
Online: 17 May 2023 (10:28:26 CEST)
The Neurodegenerative Diseases are, according to recent studies, one of the main causes of disability and death worldwide. Interest in molecular genetics has started to have an exponential growth thanks to numerous advancements in tech, shifts in the understanding of the disease as a phenomenon, and the change of perspective regarding gene editing and the upsides of this action. The aim of this paper is to analyse the newest approaches in genetics and molecular sciences regarding four of the most important neurodegenerative disorders: Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease and Amyotrophic Lateral Sclerosis. We intend through this review to focus on the newest treatment, diagnosis and predictions plans regarding this large group of diseases, in order to obtain a better accuracy analysing and spotting the emerging signs that could lead to a better outcome in order to increase both the quality and the life span of the patient. Moreover, this review could provide future evidence of possible novelty therapies that target the specific genes and could be useful to be taken into consideration when the classical approaches fail to shed light.
ARTICLE | doi:10.20944/preprints202310.0859.v1
Subject: Public Health And Healthcare, Public Health And Health Services Keywords: diabetes; Alzheimer’s disease; dementia; hospitalization
Online: 13 October 2023 (08:26:02 CEST)
Hospitalizations for patients with diabetes and dementia take a significant health and economic toll on older adults in the United States. The present study sought to examine the differences in hospitalization characteristics and outcomes associated with diabetes and dementia separately and together using discharge record data of Los Angeles County residents aged 50+ from the California Department of Health Care Access and Information for the period 2019-2021. Results from multiple linear regression analyses indicated that when compared to those with no diabetes or dementia, patients with diabetes alone exhibited the highest total charges, while those with comorbid diabetes and dementia exhibited lower charges (p≤.05). Results of a multinomial logistic regression found that patients with comorbid diabetes and dementia had the highest odds of having a length of stay of 7+ days (AOR=1.49; 95% CI=1.44-1.53). A matched-case control analysis found that comorbid diabetes and dementia was associated with significantly lower odds of hypertensive disease than diabetes alone (MOR=0.81; 95% CI=0.67-0.97). These results highlight the complexity of factors affecting variation in hospitalization outcomes across these distinct disease profiles. Findings suggest a need to carefully consider this complexity when developing health policies or strategies to improve hospitalization outcomes involving these disease conditions.
REVIEW | doi:10.20944/preprints201812.0267.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s disease; CTH gene; DNA methylation; epigenetics; epigenome-wide association study; methylome; MTHFR gene; nutrition; S-adenosylmethionine; vitamin B complex
Online: 24 December 2018 (04:48:53 CET)
DNA methylation and other epigenetic factors are important in the pathogenesis of late-onset Alzheimer’s disease (LOAD). Methylenetetrahydrofolate reductase (MTHFR) gene mutations occur in most elderly patients with memory loss. MTHFR is critical for production of S-adenosyl-L-methionine (SAM), the principal methyl donor. A common mutation (1364T/T) of the cystathionine-γ-lyase (CTH) gene affects the enzyme that converts cystathionine to cysteine in the trans-sulfuration pathway causing plasma elevation of total homocysteine (tHcy) or hyperhomocysteinemia – a strong and independent risk factor for cognitive loss and AD. Other causes of hyperhomocysteinemia include aging, nutritional factors, and deficiencies of B vitamins. We emphasize the importance of supplementing vitamin B12 (methylcobalamin), vitamin B9 (folic acid), vitamin B6 (pyridoxine), and SAM to patients in early stages of LOAD.
REVIEW | doi:10.20944/preprints201907.0265.v2
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Aging; Alzheimer’s disease; brain insulin resistance; db/db diabetic mouse model; diabetic cognopathy; insulin resistance; metabolic syndrome; mixed dementia; obesity; type 2 diabetes mellitus
Online: 9 September 2019 (06:12:15 CEST)
Type 2 diabetes mellitus (T2DM) and late-onset Alzheimer’s disease-dementia (LOAD) are increasing in global prevalence and current predictions indicate they will only increase over the coming decades. These increases may be a result of the concurrent increases of obesity and aging. T2DM is associated with cognitive impairments associated with metabolic factors and increases the cellular vulnerability to develop the age-related increased risk of LOAD. This review addresses possible mechanisms due to obesity, aging, multiple intersections between T2DM and LOAD and mechanisms for the continuum of progression. Multiple ultrastructural images in female diabetic db/db models are utilized to demonstrate marked cellular remodeling changes of mural and glia cells and provide for the discussion of functional changes in T2DM. Throughout this review multiple endeavors to demonstrate how T2DM increases the vulnerability of the brain’s neurovascular unit (NVU), neuroglia and neurons are presented. Five major intersecting links are considered: i. aging (chronic age-related diseases); ii. metabolic (hyperglycemia - advanced glycation end-products and its receptor (AGE/RAGE) interactions and hyperinsulinemia – insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen-nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis - vascular stiffening and microvascular NVU/neuroglial remodeling) with resulting impaired cerebral blood flow.
ARTICLE | doi:10.20944/preprints202003.0299.v1
Subject: Computer Science And Mathematics, Information Systems Keywords: Data Mining; Alzheimer’s Dementia; Composite Hybrid Feature Selection; Machine learning; stack Hybrid Classification; AI; MRI; Neuroimaging; MPEG7 edge histogram feature extraction; CNN
Online: 19 March 2020 (11:25:01 CET)
Alzheimer's disease (AD) detection acting as an essential role in global health care due to misdiagnosis and sharing many clinical sets with other types of dementia, and costly monitoring the progression of the disease over time by magnetic reasoning imaging (MRI) with consideration of human error in manual reading. This paper goal a comparative study on the performance of data mining techniques on two datasets of Clinical and Neuroimaging Tests with AD. Our proposed model in the first stage, Apply clinical medical dataset to a composite hybrid feature selection (CHFS), for extract new features to select the best features due to eliminating obscures features, In parallel with Apply a novel hybrid feature extraction of three batch edge detection algorithm and texture from MRI images dataset and optimized with fuzzy 64-bin histogram. In the second stage, we applied a clinical dataset to a stacked hybrid classification(SHC) model to combine Jrip and random forest classifiers with six model evaluations as meta-classifier individually to improve the prediction of clinical diagnosis. At the same stage of improving the classification accuracy of neuroimaging (MRI) dataset images by applying a convolution neural network (CNN) in comparison with traditional classifiers, running on extracted features from images. The authors have collected the clinical dataset of 426 subjects with (1229 potential patient sample) from oasis.org and (MRI) dataset from a benchmark kaggle.com with a total of around ~5000 images each segregated into the severity of Alzheimer's. The datasets evaluated using an explorer set of weka data mining software for the analysis purpose. The experimental show that the proposed model of (CHFS) feature extraction lead to effectively reduced the false-negative rate with a relatively high overall accuracy with a stack hybrid classification of support vector machine (SVM) as meta-classifier of 96.50% compared to 68.83% of the previous result on a clinical dataset, Besides a compared model of CNN classification on MRI images dataset of 80.21%. The results showed the superiority of our CHFS model in predicting Alzheimer's disease more accurately with the clinical medical dataset in early-stage compared with the neuroimaging (MRI) dataset. The results of the proposed model were able to predict with accurately classify Alzheimer's clinical samples at a low cost in comparison with the MRI-CNN images model at the early stage and get a good indicator for high classification rate for MRI images when applying our proposed model of SHC.
REVIEW | doi:10.20944/preprints202012.0079.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Mitochondria; Alzheimer’s Disease; mitophagy; neurodegeneration; aging
Online: 3 December 2020 (10:36:29 CET)
Stress mechanisms have long been associated with neuronal loss and neurodegenerative diseases. The origin of cell stress and neuronal loss likely stems from multiple pathways. These include (but are not limited to) bioenergetic failure, neuroinflammation, and loss of proteostasis. Cells have adapted compensatory mechanisms to overcome stress and circumvent death. One mechanism is mitophagy. Recent studies have implicated mitophagy in several neurodegenerative diseases and clinical trials are underway which target mitophagy pathways. Here, we review mitophagy pathways, the role of mitophagy in neurodegeneration, potential therapeutics, and the need for further study.
ARTICLE | doi:10.20944/preprints201807.0275.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: tau protein amyloids; Alzheimer’s disease; tauopathy
Online: 16 July 2018 (10:49:49 CEST)
Abnormal filamentous aggregates formed by tangled tau protein turn out to be classic amyloid fibrils, meeting all criteria defined under the fuzzy oil drop model in the context of amyloid characterization. The model recognizes amyloids as linear structures where local hydrophobicity minima and maxima propagate in an alternating manner along the fibril’s long axis. This distribution of hydrophobicity differs greatly from the classic monocentric hydrophobic core observed in globular proteins. Rather than becoming a globule, the amyloid instead forms a ribbonlike (or cylindrical) structure, which can be thought of as a distorted spherical micelle, which in limit form appears to be the ribbon-like micelle.
ARTICLE | doi:10.20944/preprints202101.0530.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Alzheimer’s disease; biomarker; prognosis; P53; mass spectrometry
Online: 26 January 2021 (10:01:35 CET)
Despite the increasing number of individuals affected by Alzheimer’s disease (AD) every year, no effective therapy has been developed to treat this neurodegenerative disease yet. The current methods for AD diagnosis are effective for clinical confirmation of the disease only when symptoms become apparent, years after molecular damage started within the patients’ brains. As higher expression of a conformationally altered p53 has been correlated with AD, we developed a mass spectrometry-based method for highly sensitive, specific, and reproducible quantification of a p53 conformational variant in plasma samples of patients with known clinical outcome. In particular, we tested the prognostic performance of an AD-specific 2D3A8-immunoselected p53 peptide (AZ 284™) in different sets of individuals progressing from both cognitively unimpaired (CU) and mild cognitive impairment (MCI) patients progressing to AD dementia. Our data showed that quantitative analysis of AZ 284™ is a reliable tool for predicting AD progression up to 6 years prior to dementia onset with AUC >90%. Taken together, these results support the implementation of p53 conformational variant quantification as an affordable and powerful diagnostic tool for early, non-invasive AD diagnosis.
ARTICLE | doi:10.20944/preprints201806.0329.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Alzheimer’s disease; Parkinson’s disease; Genetic testing; bioethics
Online: 21 June 2018 (04:38:35 CEST)
Over the last decade, advances in our understanding about the genetic architecture of complex traits and common diseases, have increased our ability to perform susceptibility genetic testing for diseases in asymptomatic individuals. These technological developments raise complex ethical, legal and social considerations. Here we discuss a series of ethical issues associated with susceptibility genetic testing for Alzheimer's and Parkinson's disease. These include, amongst others, informed consent, disclosure of results and unexpected findings, mandatory screening, privacy and confidentiality, and stigma and genetic discrimination. As knowledge of the genetic basis of these diseases continues growing, and as genetic testing becomes more widespread, we anticipate that it will become increasingly important for scientists and clinicians to engage in the conversation about the ethical, social and policy implications of these technologies.
ARTICLE | doi:10.20944/preprints202209.0235.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: lipid homeostasis; APOE4; Alzheimer’s Disease; Aβ peptide; tau
Online: 16 September 2022 (02:57:37 CEST)
The association of the APOE4 (vs APOE3) isoform with an increased risk of Alzheimer’s Disease (AD) is unequivocal, but the underlying mechanisms remain incompletely elu-cidated. A prevailing hypothesis incriminates the impaired ability of APOE4 to clear neurotoxic amyloid-β peptides (Aβ) from the brain as the main mechanism linking apolipoprotein isoform to disease aetiology. APOE protein mediates lipid transport both within the brain and from the brain to the periphery, suggesting that lipids may be potential co-factors in APOE4-associated physiopathology. The present study reveals several alterations in pathways of lipid homeostasis in the brains of mice expressing the human APOE4 versus APOE3 isoform. Carriers of APOE4 had deficient cholesterol turnover, an imbalance in the ratio of specific classes of phospholipids, lower levels of phosphatidylethanolamines bearing poly-unsaturated fatty acids and an overall eleva-tion in levels of monounsaturated fatty acids. These modifications in lipid homeostasis were related with increased production of Aβ peptides as well as augmented levels of tau and phosphorylated tau in primary neuronal cultures. This suite of AP-OE4-associated anomalies in lipid homeostasis and neurotoxic protein levels may be related to the accrued risk for AD in APOE4 carriers and provides novel insights into potential strategies for therapeutic intervention.
CONCEPT PAPER | doi:10.20944/preprints202111.0564.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: gamma-secretase; APP; Alzheimer’s disease; modelling; protein disorder
Online: 30 November 2021 (11:52:10 CET)
Proteolytic processing of amyloid precursor protein (APP) plays a critical role in pathogenesis of Azheimer’s disease (AD). Sequential cleavage of APP by β and γ secretases leads to generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2 (PS2) pay a role of catalytic subunit of γ-secretase. Multiple familial AD (FAD) mutations in APP, PS1, or PS2 result in increased Aβ42:Aβ40 ratio and accumulation of toxic Aβ42 oligomers and plaques in patient brains. In this study we performed molecular modeling of APP complex with γ-secretase and analyzed potential effects of FAD mutations in APP and PS1. We noticed that all FAD mutations in APP transmembrane domain are predicted to cause an increase in the local disorder of its secondary structure. Based on structural analysis of known γ-secretase structures we proposed that APP can form a complex with γ-secretase in 2 potential conformations – M1 and M2. In conformation M1 transmembrane domain of APP forms a contact with perimembrane domain that follows the transmembrane domain 6 (TM6) in PS1 structure. In conformation M2 transmembrane domain of APP forms a contact with transmembrane domain 7 (TM7) in PS1 structure. By analyzing effects of PS1-FAD mutations on local protein disorder index, we discovered that these mutations increase conformational flexibility of M2 and reduce conformational flexibility of M1. Based on these results we proposed that M2 conformation, but not M1 conformation, of γ secretase complex with APP leads to amyloidogenic (Aβ42-generating) processing of APP. Our model predicts that APP processing in M1 conformation is favored by a curved membranes, such as membranes of early endosomes. In contrast, APP processing in M2 conformation is likely to be favored by a relatively flat memranes such as membranes of late endosomes and plasma membrane. These predictions are consistent with published biochemical analysis of APP processing at different subcellular locations. Our results suggest that specific inhibitors of Aβ42 production could be potentially developed by selectively targeting M2 conformation of γ secretase complex with APP.
ARTICLE | doi:10.20944/preprints202102.0310.v1
Subject: Social Sciences, Psychology Keywords: physical activity; Alzheimer’s disease; 5xFAD; acute, wheel running
Online: 12 February 2021 (15:03:25 CET)
Physical activity is considered a promising preventive intervention to reduce the risk of developing Alzheimer’s disease (AD). However, the positive effect of exercise therapy has not been proven conclusively yet, likely due to confounding factors such as varying activity regimens and life or disease stages. To examine the impact of different routines of physical exercise in the early disease stages, we subjected young 5xFAD and wild-type mice to 1-day (acute) and 30-day (chronic) voluntary wheel running and compared them with age-matched sedentary controls. We observed a significant increase in brain lactate levels in acutely trained 5xFAD mice relative to all other experimental groups. Subsequent brain RNA-seq analysis did not reveal major differences in transcriptomic regulation between training durations in 5xFAD mice. In contrast, acute training yielded substantial gene expression changes in wild-type animals relative to their chronically trained and sedentary counterparts. The comparison of 5xFAD and wild-type mice showed the highest transcriptional differences in the chronic and sedentary groups, whereas acute training was associated with much fewer differentially expressed genes. In conclusion, our results suggest that different training durations did not affect the global transcriptome of 3-month-old 5xFAD mice, whereas acute running seemed to induce a similar transcriptional stress state in wild-type animals as already known for 5xFAD mice.
ARTICLE | doi:10.20944/preprints202009.0675.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Fenugreek; Alzheimer’s disease; nootropic; cognitive disorders; herbs; memory
Online: 27 September 2020 (10:45:51 CEST)
Background: Alzheimer’s disease affecting about 24 million people world-wide. The socio-economic burden on world-economies costing more than 172 billion US $ annually for the US alone. Objectives: To prepare aqueous extract of T. foenum graecum seeds (FSE) to explore the possible treatment for cognitive deficit in experimental animals. Materials and methods: FSE was subjected to preliminary phytochemical evaluation and antioxidant effect using free radical scavenging method (DPPH). All the animal behavior was video recorded with no human intervention during observation and animal groupings were blinded to avoid investigator bias. Different doses of FSE (5%, 10% and 20%), control, standard (Piracetam, 200 mg/kg, IP.) were given for male albino mice a period of 15 days followed by cognitive assessment in elevated plus maze and novel objection recognition tests. Ttransfer latencies and time exploring novel and familiar objects were recorded in respective tests. Retention of this learned-task was examined again 24 h later and inflexion ratio (IR) and discriminative index (DI) were calculated respectively. Next in the second set of experiment same groups and treatments were continued but scopolamine was administered to all the groups except normal control one hour after the last dose and examined similarly. Results: FSE showed potential antioxidant effect and a dose dependent increase in transfer latency and improved DI indicating a nootropic effect. FSE at 20% showed significant reversal of scopolamine induced dementia in the second set of experiment. Conclusion: FSE improved memory as well as reversed the chemically induced memory deficits in experimental mice.
ARTICLE | doi:10.20944/preprints202008.0716.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: amyloid beta; neuropsychological assessment; machine learning; Alzheimer’s disease
Online: 31 August 2020 (09:30:08 CEST)
Substantial studies have focused on early detection of Alzheimer's disease (AD). Cerebral amyloid beta (Aβ), is hallmark of AD, can be observed in vivo via positron emission tomography imaging using amyloid tracer or cerebrospinal fluid assessment, but costly expensive. The current study aims to identify and compared predictability in magnetic resonance imaging (MRI) markers and neuropsychological markers to predict cerebral Aβ status in AD cohort using machine learning (ML) approaches. The predictability in candidate markers for cerebral Aβ status was examined by analyzing 724 participants from the ADNI-2 cohort. Demographic variables, structural MRI markers, and neuropsychological test scores were used as input in several ML algorithms to predict cerebral Aβ positivity. Out of five combination of candidate markers, neuropsychological markers with demographics showed the most cost-efficient result. A feature selection model could distinguish abnormal levels of Aβ with the predictability of 0.85, indicating the same performance with MRI-based models. The result has first to identified the predictability in MRI markers using ML approaches, and secondary to demonstrate the neuropsychological model with demographics could predict Aβ positivity, suggesting a more cost-efficient method for detecting cerebral Aβ status compared to MRI markers.
ARTICLE | doi:10.20944/preprints202007.0645.v1
Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: Alzheimer’s disease; Tau phosphorylation; Heat stress; GSK-3β
Online: 26 July 2020 (17:04:50 CEST)
Alzheimer’s disease is a prominent neurological disorder, which leads to progressive dementia. The microtubule-associated protein Tau is been considered as one of the major causes of Alzheimer’s disease. Physiologically Tau assists in the stabilization of microtubules, contrary to this the pathological state of Tau results in the formation of neurotoxic tangles of Tau. The posttranslational modifications, such as GSK-3β-mediated Tau phosphorylation results in the generation of Tau pathology. Neuroinflammation generated in Alzheimer’s disease, contributes to elevated body temperature. The aim of present work is to study the effect of high temperature on Tau phosphorylation. The neuroblastoma cells were exposed to heat stress for 40 minutes. The immunofluorescence and western blot studies suggested that high temperature increases the levels of GSK-3β in cells. Heat stressed cells was also observed to have elevated levels of phosphorylated Tau. Additionally, heat stressed cells found to have modulated nuclear transport as the level of Ran was reduced. The results of present work suggested that increased temperature could be considered as a risk factor in Alzheimer’s disease as it elevated the GSK-3β levels in cells thus, resulting in increased Tau phosphorylation.
ARTICLE | doi:10.20944/preprints202309.2168.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: brain ischemia; Alzheimer’s disease; CA3 area; amyloid protein precursor; amyloid; α-secretase; β-secretase; presenilin 1 and 2; tau protein; genes
Online: 30 September 2023 (08:01:45 CEST)
Understanding the phenomena underlying the non-selective susceptibility to ischemia of py-ramidal neurons in the CA3 area of the hippocampus is important from the point of view of elu-cidating the mechanisms of memory loss and the development of post-ischemic dementia. We used an ischemic model of Alzheimer's disease to study changes in amyloid protein precursor gene expression, its cleavage enzymes and tau protein in the CA3 area of the hippocampus af-ter a 10-minute brain ischemia with 12, 18, and 24-month survival. Quantitative reverse tran-scriptase PCR assay showed that the expression of all the genes that contribute to amyloid pro-duction was dysregulated within 2 years in the CA3 area of the hippocampus after ischemia. The expression of the amyloid protein precursor gene was above the control values at all times of the study. The expression of the α-secretase gene also exceeded the control values throughout the study. In contrast, the expression of the β-secretase gene reaching its maximum increase 12 months after ischemia, was below control values after 18 months and again above control values after 24 months of survival. Presenilin 1 and 2 gene expression was significantly elevated throughout the follow-up period, with peak expression of both genes occurring 12 months after ischemia. This suggests that the genes studied are involved in the non-amyloidogenic processing of amyloid protein precursor. Also, tau protein gene expression was significantly elevated throughout the observation period, and peak gene expression was present 12 months after is-chemia. Data indicate that an episode of brain ischemia with long-term survival causes damage and death of pyramidal neurons in the CA3 area of the hippocampus in a manner dependent on modified tau protein. Thus defining a new and important mechanism of pyramidal neuronal death in the CA3 area after ischemia. In addition tau protein gene modification after brain is-chemia is useful in identifying ischemic mechanisms occurring in Alzheimer's disease.
ARTICLE | doi:10.20944/preprints202206.0303.v2
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: Methylmercury; Alzheimer’s; Parkinson’s; Blood-Brain Barrier; L-Cysteine; Neurotoxicity
Online: 23 June 2022 (04:26:46 CEST)
Methylmercury is a neurotoxin present in fish tissues that permeates the blood-brain barrier after consumption. Previous research has shown that methylmercury is harmful to neurons, causing pH alterations, oxidative stress, excitotoxicity, and parenchymal damage. Methylmercury is a known factor of neurological disorders including Alzheimer's and Parkinson's. The method by which methylmercury passes through the blood-brain barrier is largely unknown. According to preliminary studies, one way methylmercury crosses the blood-brain barrier is by creating a complex with L-Cysteine, which facilitates its passage by the LATs system through mimicking another amino acid existing in the body. The human blood-brain barrier was studied using C. elegans as a model organism. It was hypothesized that if methylmercury passes through the blood-brain barrier of C. elegans faster with L-Cysteine present than without L-Cysteine present, the methylmercury's adverse effects (death and locomotive difficulty) will occur sooner. Each of the four experimental groups contained one C. elegans: the control, the L-Cysteine group, the methylmercury group, and the methylmercury and L-Cysteine combination group. The effects of L-Cysteine and methylmercury on C. elegans were studied using three metrics: viability, locomotive disability, and time for locomotive effects to occur. The group that received both methylmercury and L-Cysteine had reduced viability rates and a decreased time for locomotive difficulty to develop, supporting the hypothesis. These findings suggest that L-Cysteine aids methylmercury permeation through the blood-brain barrier. Because the experiment indicates how methylmercury penetrates the blood-brain barrier, these results aid in finding a therapeutic solution to reverse methylmercury neurotoxicity in the brain. Additionally, this study further opens channels into potential therapeutic and preventative measures for dementia, improving morbidity and mortality in neurodegenerative diseases.
ARTICLE | doi:10.20944/preprints202104.0548.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: microglia; neurodegeneration; Alzheimer’s disease; neurooncology; 4R-tauopathies; TSPO-PET
Online: 20 April 2021 (13:28:14 CEST)
TSPO-PET tracers are sensitive to a single-nucleotide-polymorphism (rs6971-SNP) resulting in low (LAB), medium (MAB) and high (HAB) affinity binders, but the clinical relevance for [18F]GE-180 is still unclear. We evaluate the impact of rs6971-SNP on in vivo [18F]GE-180 binding in healthy brain and in pseudo-reference tissue in neurooncological and neurodegenerative diseases. Standardized uptake values (SUV) of [18F]GE-180-PET were assessed using a manually drawn region of interest in the fronto-parietal and cerebellar hemisphere. SUVs were compared between LAB, MAB and HAB in controls, glioma, 4-repeat tauopathies (4RT) and Alzheimer’s disease (AD) subjects. Second, SUVs were compared between patients and controls within their rs6971-subgroup. After exclusion of patients with prior therapy, n=24 LABs (n=7 controls, n=5 glioma, n=6 4RT, n=6 AD) were analysed. Age- and sex-matched MABs (n=38) and HABs (n=50) were selected. LABs had lower fronto-parietal and cerebellar SUVs when compared to MABs and HABs, but no significant difference was observed between MABs and HABs. Within each rs6971 group no SUV difference between patients and controls was detected in the pseudo-reference tissues. The rs6971-SNP affects [18F]GE-180 quantification, revealing lower binding in LABs when compared to MABs/HABs. Fronto-parietal and cerebellar ROIs were successfully validated as pseudo-reference regions.
ARTICLE | doi:10.20944/preprints202007.0532.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Phosphatidylinositol; actin remodeling; phagocytosis; dietary fatty acids; Alzheimer’s disease
Online: 22 July 2020 (14:15:35 CEST)
Alzheimer’s disease is one of the neurodegenerative diseases, characterized by the accumulation of abnormal protein deposits, which disrupt the signal transduction in neurons and other glia cells. The pathological protein Tau and amyloid-β contributes to the disrupted microglial signaling pathways, actin cytoskeleton, and cellular receptor expression. The important secondary messenger lipids i.e., phosphatidylinositols are largely affected by protein deposits of amyloid-beta in Alzheimer’s disease. Phosphatidylinositols are the product of different phosphatidylinositol kinases and the state of phosphorylation at D3, D4, and D5 positions of inositol ring. PI 3, 4, 5-P3 involves in phagocytic cup formation and relates actin remodeling whereas PI 4, 5-P2-mediates the process of phagosomes formation and further fusion with early endosome. The necessary activation of actin-binding proteins such as Rac, WAVE complex, and ARP2/3 complex for the actin polymerization in the process of phagocytosis, migration is regulated and maintained by PI 3, 4, 5-P3 and PI 4, 5-P2. Dietary fatty acids depending on their ratio and types of intake influence secondary lipid messenger along with the cellular content of phaphatidylcholine and phosphatidylethanolamine. The deposited Aβ deposits and extracellular Tau seed disrupt levels of phosphatidylinositol and actin cytoskeletal changes that hamper microglia signaling pathways in AD. We hypothesize that being a lipid species intracellular levels of phosphatidylinositol would be regulated by dietary fatty acids. We keen to understand different types of phosphatidylinositol species levels in signaling events such as phagocytosis and actin remodeling owing to the exposure of various types of dietary fatty acids.
Subject: Biology And Life Sciences, Food Science And Technology Keywords: Alzheimer’s disease; lactoferrin; cognitive function; gut microbiota; amyloid β
Online: 17 February 2020 (01:00:26 CET)
Existing evidence suggest that lactoferrin might be beneficial for Alzheimer’s disease. We aimed to determine the effects of lactoferrin intervention on cognitive function from APP/PS1 mice, and possible mechanisms involved in. Both young and middle-aged male APP/PS1 mice were divided into control and lactoferrin group with 16 weeks’ intervention. Lactoferrin intervention had no effects on cognitive function from both young and middle-aged mice, and no key markers involved in Aβ, tau pathology, neuro-inflammation and synaptic plasticity were altered post lactoferrin intervention. In regards to gut microbiota profiles, in the young mice, lactoferrin elevated α diversity index including ACE and Chao 1, and reduced the relative abundance of the genera Bacteroides and Alistipes and elevated Oscillibacter, in addition, Oscillibacter, Anaerotruncus, EF096579_g, EU454405_g, Mollicutes_RF39, EU474361_g, EU774448_g, and EF096976_g were specifically abundant post Lf intervention via LEfSe analysis. In the middle-aged mice, the relative abundance of the phylum Proteobacteria, as well as the genera Oscillospira, Coprococcus and Ruminococcus was significantly reduced post Lf intervention, additionally, S24_7, Bacteroidia, Bacteroidetes and Methylobacterium were specific via LEfSe analysis post lactoferrin intervention. In conclusion, dietary lactoferrin might be beneficial for gut microbiota homeostasis although might have no effects on cognition.
ARTICLE | doi:10.20944/preprints201808.0448.v2
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Alzheimer’s disease; Diabetes; Diet control diet; AMPK; Tau hyperphosphorylation
Online: 8 October 2018 (15:32:11 CEST)
Alzheimer’s disease (AD) is a chronic neurodegenerative disease, and typical pathologic findings include abnormally hyperphosphorylated tau aggregation and neurofibrillary tangles. Insulin resistance and hyperglycemia have been assessed as risk factors for AD development. As the maintenance of optimal blood glucose levels is an important indicator of diabetes mellitus (DM) treatment, diet control is essential. AMPK is a crucial sensor of cellular bioenergetics for controlling anabolic and catabolic metabolism. Diet restriction to achieve euglycemia can increase AMPK activity in the liver and heart. Since AMPK is a direct regulator of tau phosphorylation, we hypothesized that strict diet control to achieve euglycemia affects tau protein phosphorylation through increased AMPK activity in the hippocampus of DM rats. To confirm this hypothesis, we generated insulin-deficient DM rats by subtotal pancreatectomy. Animals were categorized into the restriction (R) group, control (C) group and ad libitum (AL) group according to the diet. We found that tau phosphorylation was significantly increased in the R group compared with the C or AL group. AMPK activity in the R group significantly increased compared to that of the C group or AL group, as expected. Furthermore, the R group showed more critical tau pathology in the hippocampus than the other groups. These results suggest that diet control to achieve euglycemia in insulin-deficient DM conditions is harmful because of the increased possibility of AD development through increased tau phosphorylation by AMPK activation in the hippocampus. We propose that not only hyperglycemia but also euglycemia, which is beneficial in DM patients, must be considered a potential risk factor for AD development, especially when euglycemia is achieved by diet control during insulin deficiency.
ARTICLE | doi:10.20944/preprints202310.0478.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: lncRNAs; MCI; SNHG16; H19; NEAT1; Alzheimer’s disease; mild cognitive impairment
Online: 9 October 2023 (11:36:08 CEST)
miRNA regulatory axes in blood of MCI patients, which includes lncRNA-SNHG16, lncRNA-H19 and lncRNA-NEAT1. Microarray investigations have demonstrated modifications in the expression of long non-coding RNAs (lncRNA) in blood of patients with MCI compared with control samples. This is the first study to explore lncRNA profiles in Mild Cognitive Impairment blood. Our study proposes RNAs targets involved in molecular pathways connected to the pathogenesis of MCI.
ARTICLE | doi:10.20944/preprints202307.2104.v1
Subject: Medicine And Pharmacology, Medicine And Pharmacology Keywords: salvia, olea europea, crocus sativus, oleuropein, trans-crocin, Alzheimer’s, neurotoxicity
Online: 31 July 2023 (10:45:57 CEST)
Neurotoxicity belongs to the leading factors inducing neurodegeneration-related diseases, such as Alzheimer’s (AD) and Parkinson’s disease. In particular, accumulation of β-amyloid proteins in the brain, a hallmark in AD, induces oxidative stress and neurotoxicity. The use of antioxidants in AD is not sufficiently effective and other pharmacological approaches tested failed to cure, prevent or retard the progression of the disease. Clinical studies indicated that several medicinal plants display beneficial effects by improving memory and cognitive functions of patients with mild and moderate AD. In this study, the potential antioxidant and neuroprotective properties of Olea europea, Crocus sativus and Salvia spp extracts, as well as their main active compounds on cell viability was evaluated using an in vitro model of AD, the differentiated human SH-SY5Y neuroblastoma cells to cholinergic neurons. Their effects were assessed against the H2O2- and β-amyloid- induced cell toxicity using the MTS test. Current findings indicated that Salvia fruticosa, S. officinalis, S. argentea leaf extracts and the active compounds, oleuropein, trans-crocin-3 and -4 display significant dose-dependent antioxidant and neuroprotective properties. It is of note though that the total phenolic fragment of Olea europea leaf extract includes several toxic compounds, such as oleocanthal, that markedly reduce cell viability and exacerbate the H2O2- and Aβ-induced cell toxicity. In addition, the Crocus sativus hydrophilic and diethyl ether extracts and all their active compounds tested markedly increased the H2O2-induced cell toxicity. In conclusion, the medicinal plants tested contain several compounds displaying dose-dependent effects against H2O2- and Aβ-induced neurotoxicity and could be used in AD, but they also contain several neurotoxic agents.
ARTICLE | doi:10.20944/preprints202209.0290.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Sulfatide; cerebroside sulfotransferase; ventricular enlargement; Alzheimer’s disease; brain MRI; aquaporins
Online: 20 September 2022 (03:56:30 CEST)
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss and a decline in activities of daily life. Ventricular enlargement has been associated with worse performance on global cognitive tests and AD. Our previous studies demonstrated that brain sulfatides, myelin-enriched lipids, are dramatically reduced in subjects at the earliest clinically recognizable AD stages via an apolipoprotein E (APOE)-dependent and isoform-specific process. Herein, we provided pre-clinical evidence that sulfatide deficiency is causally associated with brain ventricular enlargement. Specifically, taking advantage of genetic mouse models of global and adult-onset sulfatide deficiency, we demonstrated that sulfatide losses cause ventricular enlargement without significantly affecting hippocampal or whole brain volumes using histological and magnetic resonance imaging approaches. Mild decreases in sulfatide content and mild increases in ventricular areas were also observed in human APOE4 compared to APOE2 knock-in mice. Finally, we provided Western blot and immunofluorescence evidence that aquaporin-4, the most prevalent aquaporin channel in the central nervous system (CNS) that provides fast water transportation and regulates cerebrospinal fluid in the ventricles, is significantly increased under sulfatide-deficient conditions, while other major brain aquaporins (e.g., aquaporin-1) are not altered. In short, we unraveled a novel molecular mechanism that may contribute to ventricular enlargement in AD.
ARTICLE | doi:10.20944/preprints202207.0152.v1
Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: Alzheimer’s disease; oxidative stress; presenilin; mitochondria; calcium; neuronal dysfunction; Nrf2
Online: 11 July 2022 (08:03:08 CEST)
A Mitochondrial dysfunction and oxidative stress are major contributors to the pathophysiology of neurodegenerative diseases, including Alzheimer’s disease (AD). However, the mechanisms driving mitochondrial dysfunction and oxidative stress are unclear. Familial AD (fAD) is an early onset form of AD caused primarily by mutations in the presenilin-encoding genes. Previously, using Caenorhabditis elegans as a model system to study presenilin function, we found that loss of C. elegans presenilin orthologue, SEL-12, results in elevated mitochondrial and cytosolic calcium levels. Here, we provide evidence that elevated neuronal mitochondrial generated reactive oxygen species (ROS) and subsequent neurodegeneration in sel-12 mutants are a consequence of the increase of mitochondrial calcium levels and not cytosolic calcium levels. We also identify mTORC1 signaling as a critical factor in sustaining high ROS in sel-12 mutants in part through its repression of the ROS scavenging system SKN-1/Nrf. Our study reveals that SEL-12/presenilin loss disrupts neuronal ROS homeostasis by increasing mitochondrial ROS generation and elevating mTORC1 signaling, which exacerbates this imbalance by suppressing SKN-1/Nrf antioxidant activity.
ARTICLE | doi:10.20944/preprints202106.0576.v1
Subject: Chemistry And Materials Science, Analytical Chemistry Keywords: Hypericum oblongifolium; Alzheimer’s disease; Folecitin; Memory impairment; Neurodegenerative disease; Neuroprotection
Online: 23 June 2021 (11:25:28 CEST)
Neurological disorders, such as amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease, are commonly associated with persistent neuro-inflammation, and there is an urgent need to discover new therapeutic agents that may target the various pathways involved in neurodegeneration. In this study, we investigated the therapeutic potential of folecitin, a flavonoid isolated from Hypericum oblongifolium, against lipopolysaccharide (LPS)-induced oxidative stress associated with neurodegeneration, amyloidogenic Aβ production pathway, and memory dysfunction in mice. LPS was administered i.p. at 250 µg/kg/day for 3 weeks, followed by the administration of folecitin at a dose of 30 mg/kg/day for the last two weeks. A Western blot technique was used to assess the expression of different proteins involved in oxidative stress, neurodegeneration, and neuronal synapse. Results indicated that folecitin significantly reduced LPS-induced apoptotic neurodegeneration, including the expression of BAX, Caspase-3, and PARP-1 proteins, inhibited BACE1, and the amyloidogenic Aβ production pathway. Folecitin improved both pre- and post-neuronal synapse, as well as memory dysfunction. Furthermore, folecitin significantly activated endogenous antioxidant proteins such as Nrf-2 and HO-1 via stimulating the phosphorylation of Akt proteins. These findings suggest that folecitin may be a suitable lead to design new drugs for neurotoxin-triggered neurodegenerative disorders.
ARTICLE | doi:10.20944/preprints202105.0556.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Alzheimer’s disease; amyloid-beta; amyloid plaques; bacterial DNA; protein aggregation
Online: 24 May 2021 (10:33:22 CEST)
Alzheimer’s disease is associated with prion-like aggregation of the amyloid β (Aβ) peptide and the subsequent accumulation of misfolded neurotoxic aggregates in the brain. Therefore, it is critical to clearly identify the factors that trigger the cascade of Aβ misfolding and aggregation. Numerous studies have pointed out the association between microorganisms and their virulence factors and Alzheimer’s disease; however, their exact mechanisms of action remain unclear. Recently, we discovered a new pathogenic role of bacterial extracellular DNA, triggering the formation of misfolded Tau aggregates. In this study, we investigated the possible role of DNA extracted from different bacterial and eukaryotic cells in triggering Aβ aggregation in vitro. Interestingly, we found that the extracellular DNA of some, but not all, bacteria is an effective trigger of Aβ aggregation. Furthermore, the acceleration of Aβ nucleation and elongation can vary based on the concentration of the bacterial DNA and the bacterial strain from which this DNA had originated. Our findings suggest that bacterial extracellular DNA might play a previously overlooked role in the Aβ protein misfolding associated with Alzheimer’s disease pathogenesis. Moreover, it highlights a new mechanism of how distantly localized bacteria can remotely contribute to protein misfolding and diseases associated with this process. These findings might lead to the use of bacterial DNA as a novel therapeutic target for the prevention and treatment of Alzheimer’s disease.
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: copper; amyloid-β peptides; Alzheimer’s disease; oxidative stress; dopamine; neurodegeneration.
Online: 26 April 2021 (13:23:52 CEST)
The redox chemistry of copper(II) is strongly modulated by the coordination to amyloid-β peptides and by the stability of the resulting complexes. Amino terminal copper and nickel binding motifs (ATCUN) identified in truncated Aβ sequences starting with Phe4 show very high affinity for copper(II) ions. Herein, we study the oxidase activity of [Cu-Aβ4-x] and [Cu-Aβ1-x] complexes toward dopamine and other catechols. The results show that the CuII-ATCUN site is not redox-inert, the reduction of the metal is induced by coordination of catechol to the metal and occurs through an inner sphere reaction. The generation of a ternary [CuII-Aβ-catechol] species determines the efficiency of the oxidation, although the reaction rate is ruled by re-oxidation of the CuI complex. In addition to the N-terminal coordination site, the two vicinal histidines, His13 and His14, provide a second Cu-binding motif. Catechol oxidation studies together with structural insight from the mixed dinuclear complexes Ni/Cu-Aβ4-x reveal that the His-tandem is able to bind CuII ions independently of the ATCUN site, but the N-terminal metal complexation reduces the conformational mobility of the peptide chain, preventing the binding and oxidative reactivity toward catechol of CuII bound to the secondary site.
ARTICLE | doi:10.20944/preprints201805.0335.v2
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: Alzheimer’s Dementia; anaerobic neurotoxicity; inflammation; neuronal apoptosis; Non-REM Sleep
Online: 4 June 2018 (13:16:46 CEST)
Research into the causes of neurotoxicity in Alzheimer’s Dementia (AD) has focused on neurofibrillary tangles and beta amyloid (Aβ) plaques. This paper proposes the heterodox theory that these hallmarks of AD are the visible effects, not direct causes of neuronal necrosis. Rather AD results from a combination of age-induced, disproportional decline in physiological support for aerobic metabolism, and dysregulation of the sleep cycle processes. The hypothesis is that the decimation of neurons in AD results from a combination of neurotoxicity and increased apoptosis caused by: 1. direct damage from toxic waste products of anaerobic glycolysis due to a progressive decline in the capacity of neurons to perform oxidative phosphorylation (OXPHOS) and an increased reliance on anaerobic glycolysis to meet metabolic needs; 2. impaired cellular repair and effluent release due to dysregulation of non-rapid eye movement (NREM) sleep allowing damage to cell membranes and synaptic junctions to accumulate inducing a chronic inflammatory response; 3. indirect damage from products produced by inflammatory reaction to toxic metabolites; 4. neuronal apoptosis from the AβPP-mediated pathway due to the age-induced decline of growth hormone (GH), GH-releasing hormone (GHRH) and insulin-like growth factor (IGF).
ARTICLE | doi:10.20944/preprints202309.0716.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: insulin resistance; Alzheimer’s disease; ApoE4; dyslipidemia; ceramides; mitochondrial bioenergetics; cerebral cortex
Online: 12 September 2023 (14:19:04 CEST)
Alzheimer’s disease (AD) is the most common form of neurodegenerative disease worldwide. A large body of work implicates insulin resistance in the development and progression of AD such that AD may be a form of brain insulin resistance. Moreover, impairment in mitochondrial function, a common symptom of insulin resistance, now represents a fundamental aspect of AD pathobiology. Ceramides are a class of bioactive sphingolipids that have been hypothesized to drive insulin resistance. Here we describe preliminary work that tests the hypothesis that hyperinsulinemia pathologically alters cerebral mitochondrial function in AD mice via accrual of the ceramides. Homozygous male and female ApoE4 mice were given chronic injections of PBS (control), insulin, myriocin (an inhibitor of ceramide biosynthesis), or insulin and myriocin over four weeks. Cerebral ceramide content was assessed using liquid chromatography-mass spectrometry. Mitochondrial oxygen consumption rates were measured with high-resolution respirometry, and H2O2 emissions were quantified via biochemical assays on brain tissue from the cerebral cortex. Significant increases in brain ceramides and impairments in brain oxygen consumption were observed in the insulin-treated group. These hyperinsulinemia-induced impairments in mitochondrial function were reversed with the administration of myriocin. Altogether, these data demonstrate a causative role for insulin in promoting brain ceramide accrual and subsequent mitochondrial impairments that may be involved in AD expression and progression.
REVIEW | doi:10.20944/preprints202006.0203.v2
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: SH-SY5Y-derived neurons; TAU sorting; neuronal identity; tauopathy; Alzheimer’s disease
Online: 23 December 2020 (10:30:47 CET)
The microtubule-associated protein TAU is sorted into the axon in healthy brain neurons. Somatodendritic missorting of TAU is a pathological hallmark of many neurodegenerative diseases called tauopathies, including Alzheimer’s Disease (AD). Cause, consequence, and (patho)physiological mechanisms of TAU sorting and missorting are understudied, in part also due to the lack of readily available human neuronal model systems. The human neuroblastoma cell line SH-SY5Y is widely used for studying TAU physiology and TAU-related pathology in AD and related tauopathies. SH-SY5Y cells can be differentiated into neuron-like cells (SH-SY5Y-derived neurons) using various substances. This review evaluates whether SH-SY5Y-derived neurons are a suitable model for i) investigating intracellular TAU sorting in general, and ii) with respect to neuron subtype-specific TAU vulnerability. I) SH-SY5Y-derived neurons show pronounced axodendritic polarity, high levels of axonally localized TAU protein, expression of all six major human brain isoforms, and TAU phosphorylation similar to the human brain. As proliferative cells, SH-SY5Y cells are readily accessible for genetic engineering, stable transgene integration and leading-edge genome editing are valuable and promising tools for TAU-related studies. II) Depending on the used differentiation procedure, SH-SY5Y-derived neurons resemble cells of distinct subcortical nuclei, i.e. the Locus coeruleus (LC), Nucleus basalis (NB) and Substantia nigra (SN), all of which early affected in many tauopathies. This allows to analyse neuron-specific TAU isoform expression and intracellular localization, also in the context of vulnerability to TAU pathology. Limitations are e.g. the lack of mimicking age-related tauopathy risk factors and the difficulty to define the exact neuronal subtype of SH-SY5Y-derived neurons. In brief, this review discusses the suitability of SH-SY5Y-derived neurons for investigating TAU (mis)sorting mechanisms and neuron-specific TAU vulnerability in disease paradigms.
ARTICLE | doi:10.20944/preprints202011.0001.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Alzheimer’s Disease; Task Performance; Cognition; Human Activities; Amyloid Beta Protein; Dementia
Online: 2 November 2020 (08:06:39 CET)
The purpose of this study is to explore the effects of dual-task training, including cognitive tasks, on cognitive and bodily functioning and β-amyloid levels in Alzheimer's dementia patients. The subjects were 34 inpatients diagnosed with Alzheimer's dementia at a nursing hospital located in Gyeongsansi, South Korea. The patients were randomly divided into a dual-task group (n = 16) and a single-task group (n = 18). The dual-task group performed cognitive tasks at the same time as exercising tasks, while the single-task group performed only exercise tasks. Each group was trained for 30 minutes three times a week for eight weeks. The Mini-Mental State Examination was used to measure the patients’ cognitive function. Static and dynamic balance were measured to evaluate bodily functioning. Static balance was measured using Biorescue, while dynamic balance was measured using the Berg Balance Scale. Blood analysis was performed to measure levels of β-amyloid, which is known to cause Alzheimer's dementia. Both groups exhibited statistically significant improvements in gait function after the training (p < .05). The dual-task group exhibited statistically significant differences in cognitive function, static and dynamic balance function, and β-amyloid levels after training (p < .05). A significant difference was observed between the two groups (p < .05). Dual-task activities were found to be effective in improving cognitive and bodily functioning and reducing β-amyloid levels in Alzheimer's dementia patients. Therefore, dual-task training is thought to be an effective method of treating and preventing Alzheimer's dementia.
REVIEW | doi:10.20944/preprints201907.0289.v1
Subject: Medicine And Pharmacology, Dietetics And Nutrition Keywords: omega-3 polyunsaturated fatty acids; Parkinson’s disease; Alzheimer’s disease; clinical trials
Online: 25 July 2019 (11:38:57 CEST)
A nutritional approach could be a promising strategy to prevent or slow the progression of neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, since there is no effective therapy for these diseases so far. The beneficial effects of omega-3 fatty acids are now well established by a plethora of studies through their involvement in multiple biochemical functions, including synthesis of antinflammatory mediators, cell membrane fluidity, intracellular signalling and gene expression. This systematic review will consider epidemiological studies and clinical trials that assessed the impact of supplementation or dietary intake of omega-3 polyunsaturated fatty acids on neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. Indeed, treatment with omega-3 fatty acids, being safe and well tolerated, represent a valuable and biologically plausible tool in the management of neurodegenerative diseases in their early stages.
ARTICLE | doi:10.20944/preprints201810.0022.v1
Subject: Public Health And Healthcare, Physical Therapy, Sports Therapy And Rehabilitation Keywords: Alzheimer’s disease; dementia; therapeutic environment; Virtual reality; Stress recovery; therapeutic gardens
Online: 2 October 2018 (11:03:03 CEST)
Purpose: This paper extends previous works to include the role of therapeutic gardens in the healing environment as an intervention for bettering the clinical outcomes of Alzheimer’s and dementia patients, the positive impact of healing gardens and the innovative application of technologies with nature, for promoting cognitive rehabilitation in this particular patient population.Methods: Using ISI Web of Science, PubMed, ProQuest Central, MEDLIN, Scopus and Google Scholar, a relevant literature search on the positive health implications of therapeutic gardens on Alzheimer’s and dementia patients’ in the healthcare milieu was conducted.Results: Health implication of therapeutic gardens on Alzheimer’s and dementia patients’ spans across physical, social, psychological and cognitive effects. Virtual reality (VR) technologies offer positive cognitive outcomes to Alzheimer's disease (AD) and dementia patients.Conclusion: Therapeutic gardens should be extended for speedier recovery of other patient populations. Future directions in the design of healthcare gardens with a focus on patient experience are inferred.
REVIEW | doi:10.20944/preprints202307.1923.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: Alzheimer’s disease; Parkinson’s disease; phytochemicals; dietary intervention; epigenetics; transcriptome; epigenome; transcriptomics; epigenomics
Online: 27 July 2023 (13:22:59 CEST)
Neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, are caused by a combination of multiple events that damage neuronal function. A well-characterized biomarker of neurodegeneration is proteinaceous aggregates accumulation in the brain. However, the gradually worsening symptoms of neurodegenerative diseases are unlikely to be solely due to the result of a mutation in a single gene, but rather a multi-step process involving epigenetic changes. Multiple epigenetic studies have revealed that modification of histones accompanied by both the local and global remodeling of the chromatin structure and alternations in transcriptional patterns are closely associated with the pathogenesis of neurodegenerative diseases. Unlike DNA mutations, epigenetic alterations are reversible, and therefore raise the possibilities for therapeutic intervention including dietary modifications. Additionally, reactive oxygen species may contribute to the pathogenesis of Alzheimer’s disease and Parkinson’s disease. Given that the antioxidant properties of plant-derived phytochemicals are likely to exhibit pleiotropic effects against ROS-mediated epigenetic alternation, dietary intervention may be promising for the management of neurodegeneration in these diseases. In this review, the state-of-the-art applications using single-cell multi-modal omics approaches including genetics, and epigenetics, and dietary approaches for the identification of novel biomarkers and therapeutic approaches for the treatment of neurodegenerative diseases are discussed.