Impact of Action Observation Therapy along with Usual Physiotherapy Intervention of Individual with Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive impairments in the initial stage, which lead to severe cognitive dysfunction in the later stage. Action observation therapy (AOT) is a multisensory cognitive rehabilitation technique where the patient initially observes the actions and then tries to perform. The study aimed to examine the impact of AOT along with usual physiotherapy interventions to reduce depression, improve cognition and balance of a patient with AD. A 67 years old patient with AD was selected for this study because the patient has been suffering from depression, dementia, and physical dysfunction along with some other health conditions like diabetes and hypertension. Before starting intervention, a baseline assessment was done through the Beck Depression Inventory (BDI) tool, the Mini-Cog Scale, and the Berg Balance Scale (BBS). The patient received 12 sessions of AOT along with usual physiotherapy interventions thrice a week for four weeks, which included 45 minutes of each session. After four weeks of intervention, the patient demonstrated significant improvement in depression, cognition, and balance, whereas the BDI score declined from moderate 21/63 to mild 15/63 level of depression. The Mini-Cog score improved from 2/5 to 4/5, and the BBS score increased from 18/56 to 37/56. It is concluded that AOT along with usual physiotherapy intervention helps to reduce depression, improve cognition and balance of people with AD.

Neural stem cells promote neuroplasticity: a promising therapeutic strategy for the treatment of Alzheimer’s disease

Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheimer’s disease.Hence,promoting neuroplasticity may represent an effective strategy with which Alzheimer’s disease can be alleviated.Due to their significant ability to self-renew,differentiate,and migrate,neural stem cells play an essential role in reversing synaptic and neuronal damage,reducing the pathology of Alzheimer’s disease,including amyloid-β,tau protein,and neuroinflammation,and secreting neurotrophic factors and growth factors that are related to plasticity.These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain.Consequently,neural stem cells are considered to represent a potential regenerative therapy with which to improve Alzheimer’s disease and other neurodegenerative diseases.In this review,we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating Alzheimer’s disease in the clinic.

Emerging Novel Therapeutic Approaches for the Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is caused by synaptic failure and the excessive accumulation of misfolded proteins especially Aβ and tau, and associated with memory loss and cognitive impairment. Treatment of AD mainly consists of symptomatic therapy and disease-modifying therapy (DMT). Several monotherapies including small molecules or antibodies have been evaluated through multiple clinical trials, but a very few have been approved by the USFDA to intervene the disease’s pathogenesis. Past research has shown multifactorial nature of AD, therefore, multi-target drugs were proposed to target different pathways at the same time, however, currently no rationally designed multi-target directed ligand (MTDL) has been clinically approved. Different combinations and bispecific antibodies are also under development. Novel approaches like stem cell-based therapies, microRNAs, peptides, ADCs and vaccines cast a new hope for AD treatment, however, a number of questions remained to be answered prior to their safe and effective clinical translation. This review explores the small molecules, MTDL, and antibodies (monospecific and bispecific) for the treatment of AD. Finally, future perspectives (stem cell therapy, PROTAC approaches, microRNAs, ADC, peptides and vaccines) are also discussed with regard to their clinical applications and feasibility.

Nanotechnology-based gene therapy as a credible tool in the treatment of Alzheimer’s disease

Toxic aggregated amyloid-βaccumulation is a key pathogenic event in Alzheimer’s disease.Treatment approaches have focused on the suppression,deferral,or dispersion of amyloid-βfibers and plaques.Gene therapy has evolved as a potential therapeutic option for treating Alzheimer’s disease,owing to its rapid advancement over the recent decade.Small interfering ribonucleic acid has recently garnered considerable attention in gene therapy owing to its ability to down-regulate genes with high sequence specificity and an almost limitless number of therapeutic targets,including those that were once considered undruggable.However,lackluster cellular uptake and the destabilization of small interfering ribonucleic acid in its biological environment restrict its therapeutic application,necessitating the development of a vector that can safeguard the genetic material from early destruction within the bloodstream while effectively delivering therapeutic genes across the bloodbrain barrier.Nanotechnology has emerged as a possible solution,and several delivery systems utilizing nanoparticles have been shown to bypass key challenges regarding small interfering ribonucleic acid delivery.By reducing the enzymatic breakdown of genetic components,nanomaterials as gene carriers have considerably enhanced the efficiency of gene therapy.Liposomes,polymeric nanoparticles,magnetic nanoparticles,dendrimers,and micelles are examples of nanocarriers that have been designed,and each has its own set of features.Furthermore,recent advances in the specific delivery of neurotrophic compounds via gene therapy have provided promising results in relation to augmenting cognitive abilities.In this paper,we highlight the use of different nanocarriers in targeted gene delivery and small interfering ribonucleic acid-mediated gene silencing as a potential platform for treating Alzheimer’s disease.

The neuroprotective effects of oxygen therapy in Alzheimer’s disease:a narrative review

Alzheimer’s disease(AD)is a degenerative neurological disease that primarily affects the elderly.Drug therapy is the main strategy for AD treatment,but current treatments suffer from poor efficacy and a number of side effects.Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD.Hypoxia is one of the important factors that contribute to the pathogenesis of AD.Multiple cellular processes synergistically promote hypoxia,including aging,hypertension,diabetes,hypoxia/obstructive sleep apnea,obesity,and traumatic brain injury.Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD,such as amyloid-beta metabolism,tau phosphorylation,autophagy,neuroinflammation,oxidative stress,endoplasmic reticulum stress,and mitochondrial and synaptic dysfunction.Treatments targeting hypoxia may delay or mitigate the progression of AD.Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD.Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism,tau phosphorylation,neuroinflammation,neuronal apoptosis,oxidative stress,neurotrophic factors,mitochondrial function,cerebral blood volume,and protein synthesis.In this review,we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations.We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Presymptomatic Diagnosis and Gene Therapy for Alzheimer’s Disease: Genomic, Therapeutic, and Ethical Aspects—A Systematic Review

Over the past three decades, genomic and epigenetic sciences have identified more than 70 genes involved in the molecular pathophysiology of Alzheimer’s disease (AD). DNA methylation, abnormal histone and chromatin regulation and the action of various miRNAs induce AD. The identification of mutated genes has paved the way for the development of diagnostic kits and the initiation of gene therapy trials. However, despite major advances in neuroscience research, there is yet no suitable treatment for AD. Therefore, the early diagnosis of this neurodegenerative disease raises several ethical questions, including the balance between the principle of non-maleficence and the principle of beneficence. The aims of this research were to present the genomic and ethical aspects of AD, and to highlight the ethical principles involved in its presymptomatic diagnosis and therapy. A systematic review of the literature in PubMed, Google Scholar and Science Direct was carried out to outline the genomic aspects and ethical principles relating not only to the presymptomatic diagnosis of AD, but also to its gene therapy. A total of 16 publications were selected. AD is a multifactorial disease that can be genetically classified into Sporadic Alzheimer’s Disease and Familial Alzheimer’s Disease based on family history. Gene therapy targeting specific disease-causing genes is a promising therapeutic strategy. Advancements in artificial intelligence applications may enable the prediction of AD onset several years in advance. While early diagnosis of AD may empower patients with full decision competence for early decision-making, it also carries implications for the patient’s family members, who are at risk of developing the disease, potentially becoming a source of confusion or anxiety. AD has a significant impact on the life of individuals at risk and their families. Given the absence of disease modifying therapy, genetic screening and early diagnosis for this condition raise ethical issues that must be carefully considered in the context of fundamental bioethical principles, including autonomy, beneficence, non-maleficence, and justice.

Extracellular vesicles in Alzheimer’s disease:from pathology to therapeutic approaches

Alzheimer’s disease is a progressive and fatal neurodegenerative disorder that starts many years before the onset of cognitive symptoms.Identifying novel biomarkers for Alzheimer’s disease has the potential for patient risk stratification,early diagnosis,and disease monitoring in response to therapy.A novel class of biomarkers is extracellular vesicles given their sensitivity and specificity to specific diseases.In addition,extracellular vesicles can be used as novel biological therapeutics given their ability to efficiently and functionally deliver therapeutic cargo.This is critical given the huge unmet need for novel treatment strategies for Alzheimer’s disease.This review summarizes and discusses the most recent findings in this field.

Acquired immunity and Alzheimer's disease

Alzheimer’s disease(AD) is an age-related neurodegenerative disease characterized by progressive cognitive defects. The role of the central immune system dominated by microglia in the progression of AD has been extensively investigated. However, little is known about the peripheral immune system in AD pathogenesis.Recently, with the discovery of the meningeal lymphatic vessels and glymphatic system, the roles of the acquired immunity in the maintenance of central homeostasis and neurodegenerative diseases have attracted an increasing attention. The T cells not only regulate the function of neurons, astrocytes, microglia, oligodendrocytes and brain microvascular endothelial cells, but also participate in the clearance of β-amyloid(Aβ) plaques. Apart from producing antibodies to bind Aβ peptides, the B cells affect Aβ-related cascades via a variety of antibodyindependent mechanisms. This review systemically summarizes the recent progress in understanding pathophysiological roles of the T cells and B cells in AD.

Effects of medicinal plants on Alzheimer＇s disease and memory deficits

Alzheimer＇s disease is an age-related neurodegenerative disorder characterized by memory deficits. Various studies have been carried out to find therapeutic approaches for Alzheimer＇s disease. However, the proper treatment option is still not available. There is no cure for Alzheimer＇s disease, but symptomatic treatment may improve the memory and other dementia related problems. Traditional medicine is practiced world- wide as memory enhancer since ancient times. Natural therapy including herbs and medicinal plants has been used in the treatment of memory deficits such as dementia, amnesia, as well as Alzheimer＇s disease since a long time. Medicinal plants have been used in different systems of medicine, particularly Unani system of medicines and exhibited their powerful roles in the management and cure of memory disorders. Most of herbs and plants have been chemically evaluated and their efficacy has also been proven in clinical trials. However, the underlying mechanisms of actions are still on the way. In this paper, we have reviewed the role of different medicinal plants that play an important role in the treatment of Alzheimer＇s disease and memory deficits using conventional herbal therapy.

Advances in Drug Therapy for Alzheimer’s Disease

Alzheimer’s disease(AD)is a chronic neurodegenerative disease that mainly causes dementia.It is a serious threat to the health of the global elderly population.Considerable money and effort has been invested in the development of drug therapy for AD worldwide.Many drug therapies are currently under development or in clinical trials,based on two known mechanisms of AD,namely,Aβtoxicity and the abnormal Tau hyperphosphorylation.Numerous drugs are also being developed for other AD associated mechanisms such as neuroinflammation,neurotransmitter imbalance,oxidative damage and mitochondrial dysfunction,neuron loss and degeneration.Even so,the number of drugs that can successfully improve symptoms or delay the progression of the disease remains very limited.However,multi-drug combinations may provide a new avenue for drug therapy for AD.In addition,early diagnosis of AD and timely initiation of treatment may allow drugs that act on the early pathological processes of AD to help improve the symptoms and prevent the progression of the condition.

Hyperbaric oxygen therapy as a new treatment approach for Alzheimer's disease

Hyperbaric oxygen therapy as a new treatment approach for Alzheimer’s disease（AD）：Alongside the increase in life expectancy,the prevalence of age-related disorders,such as neurodegenerative diseases,is on the rise.For example,AD,the most common form of dementia in the elderly,accounts for 60–80%of all dementia cases.

A Case of Alzheimer’s Disease Was Kept Relative Stable with Sequential Therapy for Eight Years

Background: Although Alzheimer’s disease (AD) has been intensively investigated for many years, the effective treatments are largely missing. Commonly used conventional therapy, such as cholinesterase inhibitors (ChEI) and N-methyl D-asparate receptor antagonist, have been generally considered as having symptom-relieving rather than disease-modifying effects. Thus, how to improve cognitive function beyond such effect & time limitations has become a serious challenge. Aim: In order to solve this challenge, a sequential therapy with the integration of conventional therapy and herbal therapy was applied to AD patients. Careful clinical observation was conducted in our outpatient setting. Case Presentation: A case of probable AD received the sequential therapy has achieved relative stable cognition and overall status in eight years. Conclusion: During the treatment of this AD case in eight years, sequential therapy showed great potential in stabilizing and improving cognition and overall status. Well designed preclinical and clinical studies are needed to investigate the efficacy of sequential therapy for AD and other type of dementia.

Mesenchymal stem cells:As a multi-target cell therapy for clearingβ-amyloid deposition in Alzheimer’s disease

Extracellularβ-amyloid(Aβ)plaques and neurofibrillary tangles(NFTs)are the pathological hallmarks of Alzheimer’s disease(AD).Studies have shown that aggregates of extracellular Aβcan induce neuroinflammation mediated neurotoxic signaling through microglial activation and release of pro-inflammatory factors.Thus,modulation of Aβmight be a potential therapeutic strategy for modifying disease progression.Recently,a large number of reports have confirmed the beneficial effects of mesenchymal stem cells(MSCs)on AD.It is believed to reduce neuroinflammation,reduce Aβamyloid deposits and NFTs,increase acetylcholine levels,promote neurogenesis,reduce neuronal damage,and improve working memory and cognition.In this review,we focus on the role of MSCs in clearing Aβdeposition.MSCs have the potential to modulate Aβ-related microenvironments via enhancement of autophagy,proteolysis of Aβaggregates,phagocytic clearance of Aβby microglial M2 polarization,decrease oxidative stress(OS),and correction of abnormal sphingolipid(SL)metabolism.With advantages in clinical applications,these data suggest that the use of MSCs as a multi-target modulator of Aβwould be an effective therapeutic approach in AD.

EEG Analysis of the Contribution of Music Therapy and Virtual Reality to the Improvement of Cognition in Alzheimer’s Disease

Alzheimer’s disease is the most common form of dementia, affecting nearly 9.9 million new people every year. The disease provokes important memory and cognitive impairment, eventually causing individuals to forget their loved ones and rendering them completely dependent on their caretakers. Alzheimer’s patients typically experience more negative emotions, such as frustration and apathy, than healthy older adults. There is currently no cure for the disease. Our research group explores how the integration of virtual reality (VR) and an EEG-based intelligent agent in music therapy can alleviate psychological and cognitive symptoms of the disease. We propose a theory explaining how, through activation of the brain reward system, music can reduce negative emotions, increase positive emotions and as a result increase performance on cognitive tasks. The results of our experimental study concord with our theory: emotional states of participants are improved, as per recorded through EEG, and performances on memory tasks show improvement following the intervention. We believe that the combination of EEG brain assessment, VR and music therapy is a promising method for emotional states and cognitive symptoms of Alzheimer’s disease.

Effects of <i>Syzygium cumini</i>Seed Extract on the Memory Loss of Alzheimer’s Disease Model Rats

Alzheimer’s disease (AD) is the most prominent dementia-related disease and characterized by the presence of insoluble amyloid beta peptide (Aβ) fibers in or around the brain neurons of the affected person. Therefore, agent(s) capable of inhibiting brain amyloid deposition might delay the occurrence or retard the progress forwards of AD and related neurobehavioral symptoms. Here, we report whether, chronic oral administration of Syzygium cumini (locally known as Jam)-seed extract exerts protection against the progressive cognitive decline in the Aβ1-40-infused AD model rats. After 12 weeks of feeding with S. cumini seed extract (at 300 mg/kg BW), we evaluated the learning-related memory of the rats by 8-arm radial maze task, where we determined two types of memory errors, namely reference memory errors (RMEs) and working memory errors (WMEs). After completion of memory tests, rats were sacrificed and the levels of lipid peroxide (LPO), the Aβ1-40-burden, Aβ1-40-oligomers, proinflammatory TNFα, brain derived neurotrophic factor (BDNF), Tyrosine-kinase B (TrkB), postsynaptic-density protein 95 (PSD-95) and Synapse-associated protein (SNAP-25) were determined in the corticohippocampal tissues of the brain. In addition, in vitro antioxidative effects of S. cumini seed extract were evaluated. The oral administration of S. cumini extract significantly increased the memory-related learning ability of the AD model rats, concomitantly with reductions in the levels of corticohippocampal Aβ1-40-burden and Aβ1-40-oligomers. Furthermore, the extract suppressed the levels of TNFα and LPO in the corticohippocampal tissues of the AD rats and also the later in the plasma, suggesting an anti-oxidative and anti-inflammatory activities of the S. cumini extract in the brains of AD model rats. S. cumini extract also increased the levels of brain cognition and memory-related proteins, including BDNF, TrKB, PSD-95 and SNAP-25. We thus suggest that S. cumini-seed extract could be used in neurobehavioral deficits and associated pathogenesis of Alzheimer’s disease.

A Hopfield-like hippocampal CA3 neural network model for studying associative memory in Alzheimer's disease

Associative memory, one of the major cognitive functions in the hippocampal CA3 region, includes auto-associative memory and hetero-associative memory. Many previous studies have shown that Alzheimer＇s disease （AD） can lead to loss of functional synapses in the central nervous system, and associative memory functions in patients with AD are often impaired, but few studies have addressed the effect of AD on hetero-associative memory in the hippocampal CA3 region. In this study, based on a simplified anatomical structure and synaptic connections in the hippocampal CA3 region, a three-layered Hopfield-like neural network model of hippocampal CA3 was proposed and then used to simulate associative memory functions in three circumstances： normal, synaptic deletion and synaptic compensation, according to Ruppin＇s synaptic deletion and compensation theory. The influences of AD on hetero-associative memory were further analyzed. The simulated results showed that the established three-layered Hopfield-like neural network model of hippocampal CA3 has both auto-associative and hetero-associative memory functions. With increasing synaptic deletion level, both associative memory functions were gradually impaired and the mean firing rates of the neurons within the network model were decreased. With gradual increasing synaptic compensation, the associative memory functions of the network were improved and the mean firing rates were increased. The simulated results suggest that the Hopfield-like neural network model can effectively simulate both associative memory functions of the hippocampal CA3 region. Synaptic deletion affects both auto-associative and hetero-associative memory functions in the hippocampal CA3 region, and can also result in memory dysfunction. To some extent, synaptic compensation measures can offset two kinds of associative memory dysfunction caused by synaptic deletion in the hippocampal CA3 area.

Tetrahydrohyperforin(IDN5706) targets the endoplasmic reticulum for autophagy activation： potential mechanism for Alzheimer＇s disease therapy

Alzheimer’s disease（AD）is the most common form of dementia worldwide among the older population.To date,there is no therapy to stop the destruction of brain cells and all the available treatments only compensate for the loss of synaptic transmission,thus resulting in marginal benefits to patients.

Cell-based therapy in Alzheimer's disease: can human fetal cholinergic neurons “untangle the skein”?

Alzheimer＇s disease（AD）is a devastating neurodegenerative disorder and the most common form of old-age dementia.The disease is characterized by a progressive decline in cognitive functions,gradual loss of memory and ability to perform everyday activities,and leads to inevitable death within 3 to 9 years atter diagnosis.

The CircRNAs for Diagnostic, Prognostic, and Therapy in Alzheimer’s Disease

The structure and biological function of circular RNAs (circRNAs) in regulating gene expression in a cell is far from known. CircRNAs are unique molecules that contain potent regulatory elements. CircRNAs actively interact with miRNAs (sponging), affecting their regulation and functions. In addition, circRNAs have roles in transcriptional regulation, splicing, and peptide synthesis. With all these properties, circRNAs could play an essential role in diseases, especially Alzheimer’s. Their role in early diagnosis, previous to present symptoms, prognosis associated with neuropathological AD of specific circRNAs, and one of their primary functions is to act as a sponge for miRNAs, which could be a starting point for future gene therapy. This review aims to summarize the current knowledge of these exciting molecules and their potential use as new markers for AD risk. This article will focus on circRNAs deregulated in Alzheimer’s.

Methodological quality evaluation of systematic reviews of music therapy for Alzheimer’s disease in the recent five years

Aims:This study aims to investigate the methodological quality of the systematic reviews of music therapy for Alzheimer’s Disease in the past five years,and to explore their compliance with each AMSTAR(A Measure Tool to Assess Systematic Reviews)item.Based on the above,this study is intended to facilitate the evidence transformation of music therapy in Alzheimer's Disease.Method:Cochrane Library,Web of Science,Embase and PubMed were searched from 2017-2021,to obtain the systematic reviews of music therapy among Alzheimer’s Disease.We used the AMSTAR,to evaluate their methodological quality.Additionally,their compliance with 16 AMSTAR items was investigated.Results:12 systematic reviews were included in this study.The methodological quality of 10 articles was“very low”,1 article was“low”,and 1 article was“high”.The 12 systematic reviews had 25%to 100%compliance with 16 AMSTAR items.Conclusion:The methodological quality of systematic reviews of music therapy among Alzheimer’s Disease in the recent five years is not high,and needs to be further improved.Future research should continue to explore the factors that affect their methodological quality,to promote the transformation of evidence-based evidence.