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Non-Linear Association between FolateVitamin B12 Status and Cognitive Function in Older Adults.

Although folate and vitamin B12 status have long been implicated in cognitive function, there is no consensus on the threshold of folate and vitamin B12 for assessing their impacts on cognition. The goal of this study was to detail the association between folate and vitamin B12 with cognitive performance. We analyzed cross-sectional data of older adults (≥60 y

Red Blood Cell DHA Is Inversely Associated with Risk of Incident Alzheimers Disease and All-Cause Dementia Framingham Offspring Study.

Docosahexaenoic acid (DHA) might help prevent Alzheimers disease (AD). Red blood cell (RBC) status of DHA is an objective measure of long-term dietary DHA intake. In this prospective observational study conducted within the Framingham Offspring Cohort (1490 dementia-free participants aged ≥65 years old), we examined the association of RBC DHA with incident AD, testing for an interaction with

Modulation of Gut Microbiota and Neuroprotective Effect of a Yeast-Enriched Beer.

Beer is the most consumed alcoholic beverage worldwide. It is rich in nutrients, and with its microbial component it could play a role in gut microbiota modulation. Conflicting data are currently available regarding the consequences of alcohol and alcohol-containing beverages on dementia and age-associated disorders including Alzheimers disease (AD), a neurodegeneration characterized by protein aggregation, inflammatory processes and alterations of components of the gut-brain axis. The effects of an unfiltered and unpasteurized craft beer on AD molecular hallmarks, levels of gut hormones and composition of micromycobiota were dissected using 3xTg-AD mice. In addition, to better assess the role of yeasts, beer was enriched with the same

Pore Formation Mechanism of A-Beta Peptide on the Fluid Membrane A Combined Coarse-Grained and All-Atomic Model.

In Alzheimers disease, ion permeability through the ionic channel formed by Aβ peptides on cellular membranes appears to underlie neuronal cell death. An understanding of the formation mechanism of the toxic ionic channel by Aβ peptides is very important, but remains unclear. Our simulation results demonstrated the dynamics and mechanism of channel formation by Aβ1-28 peptides on the DPPC and POPC membrane by the coarse-grained method. The ionic channel formation is driven by the gyration of the radius and solvent accessible molecular surface area of Aβ1-28 peptides. The ionic channel formation mechanism was explored by the free energy profile based on the distribution of the gyration of the radius and solvent accessible molecular surface area of Aβ1-28 peptides on the fluid membrane. The stability and water permeability of the ionic channel formed by Aβ peptides was investigated by all-atomic model simulation. Our simulation showed that the ionic channel formed by Aβ1-28 peptides is very stable and has a good water permeability. This could help us to understand the pore formation mechanism by Aβ1-28 peptides on the fluidic membrane. It also provides us with a guideline by which to understand the toxicity of Aβ1-28 peptides pores to the cell.

Green Tea (

Objectives Green tea (

1,8-Cineole Ameliorates Advanced Glycation End Products-Induced Alzheimers Disease-like Pathology In Vitro and In Vivo.

Advanced glycation end products (AGEs) are stable products produced by the reaction of macromolecules such as proteins, lipids or nucleic acids with glucose or other reducing monosaccharides, which can be identified by immunohistochemistry in the senile plaques and neurofibrillary tangles of Alzheimers disease (AD) patients. Growing evidence suggests that AGEs are important risk factors for the development and progression of AD. 1,8-cineole (CIN) is a monoterpenoid compound which exists in many plant essential oils and has been proven to have neuroprotective activity, but its specific effect and molecular mechanisms are not clear. In this study, AGEs-induced neuronal injury and intracerebroventricular-AGE animals as the possible models for AD were employed to investigate the effects of CIN on AD pathology as well as the molecular mechanisms involved both in vivo and in vitro. Our study demonstrated that CIN could ameliorate tau phosphorylation by down-regulating the activity of GSK-3β and reducing Aβ production by inhibiting the activity of BACE-1 both in vivo and in vitro. It is suggested that CIN has certain therapeutic value in the treatment of AD.

Curcumin Scaffold as a Multifunctional Tool for Alzheimers Disease Research.

Alzheimers disease (AD) is one of the most common neurodegenerative disorders, which is caused by multi-factors and characterized by two histopathological hallmarks amyloid-β (Aβ) plaques and neurofibrillary tangles of Tau proteins. Thus, researchers have been devoting tremendous efforts to developing and designing new molecules for the early diagnosis of AD and curative purposes. Curcumin and its scaffold have fluorescent and photochemical properties. Mounting evidence showed that curcumin scaffold had neuroprotective effects on AD such as anti-amyloidogenic, anti-inflammatory, anti-oxidative and metal chelating. In this review, we summarized different curcumin derivatives and analyzed the in vitro and in vivo results in order to exhibit the applications in AD diagnosis, therapeutic monitoring and therapy. The analysis results showed that, although curcumin and its analogues have some disadvantages such as short wavelength and low bioavailability, these shortcomings can be conquered by modifying the structures. Curcumin scaffold still has the potential to be a multifunctional tool for AD research, including AD diagnosis and therapy.

Neuroprotective Effect of Caffeine in Alzheimers Disease.

Alzheimers disease (AD) is the leading cause of dementia, predicted to be the most significant health burden of the 21st century, with an estimated 131.5 million dementia patients by the year 2050. This review aims to provide an overview of the effect of caffeine on AD and cognition by summarizing relevant research conducted on this topic. We searched the Web of Science core collection and PubMed for studies related to the effect of caffeine on AD and cognition using title search terms caffeine coffee Alzheimers cognition. There is suggestive evidence from clinical studies that caffeine is neuroprotective against dementia and possibly AD (20 out of 30 studies support this), but further studies, such as the ideal study proposed in this review, are required to prove this link. Clinical studies also indicate that caffeine is a cognitive normalizer and not a cognitive enhancer. Furthermore, clinical studies suggest the neuroprotective effect of caffeine might be confounded by gender. There is robust evidence based on in vivo and in vitro studies that caffeine has neuroprotective properties in AD animal models (21 out of 22 studies support this), but further studies are needed to identify the mechanistic pathways mediating these effects.

Expatiating the Pharmacological and Nanotechnological Aspects of the Alkaloidal Drug Berberine Current and Future Trends.

Traditionally, herbal compounds have been the focus of scientific interest for the last several centuries, and continuous research into their medicinal potential is underway. Berberine (BBR) is an isoquinoline alkaloid extracted from plants that possess a broad array of medicinal properties, including anti-diarrheal, anti-fibrotic, antidiabetic, anti-inflammatory, anti-obesity, antihyperlipidemic, antihypertensive, antiarrhythmic, antidepressant, and anxiolytic effects, and is frequently utilized as a traditional Chinese medicine. BBR promotes metabolisms of glucose and lipids by activating adenosine monophosphate-activated protein kinase, stimulating glycolysis and inhibiting functions of mitochondria all of these ameliorate type 2 diabetes mellitus. BBR has also been shown to have benefits in congestive heart failure, hypercholesterolemia, atherosclerosis, non-alcoholic fatty liver disease, Alzheimers disease, and polycystic ovary syndrome. BBR has been investigated as an interesting pharmacophore with the potential to contribute significantly to the research and development of novel therapeutic medicines for a variety of disorders. Despite its enormous therapeutic promise, the clinical application of this alkaloid was severely limited because of its unpleasant pharmacokinetic characteristics. Poor bioavailability, limited absorption, and poor water solubility are some of the obstacles that restricted its use. Nanotechnology has been suggested as a possible solution to these problems. The present review aims at recent updates on important therapeutic activities of BBR and different types of nanocarriers used for the delivery of BBR in different diseases.

Alzheimers Disease CSF Biomarker Profiles in Idiopathic Normal Pressure Hydrocephalus.

Patients with idiopathic normal pressure hydrocephalus (iNPH) frequently show pathologic CSF Aβ

StatPearls

Cognition is the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses. It encompasses various aspects of high-level intellectual functions and processes such as attention, memory, knowledge, decision-making, planning, reasoning, judgment, perception comprehension, language, and visuospatial function. Cognitive processes use existing knowledge and generate new knowledge. Cognitive deficit is an inclusive term used to describe the impairment of different domains of cognition. Cognitive deficit is not limited to any particular disease or condition but may be one of the manifestations of someones underlying condition. It is also used interchangeably with cognitive impairment. It might be a short-term condition or a progressive and permanent entity. On the other hand, cognitive disorders are a bigger entity, which is a part of neurocognitive disorders (DSM-5). Cognitive disorders are defined as any disorder that significantly impairs the cognitive functions of an individual to the point where normal functioning in society is impossible without treatment. Alzheimer disease is the most well-known condition associated with cognitive impairment.

Predictive Scale for Amyloid PET Positivity Based on Clinical and MRI Variables in Patients with Amnestic Mild Cognitive Impairment.

The presence of amyloid-β (Aβ) deposition is considered important in patients with amnestic mild cognitive impairment (aMCI), since they can progress to Alzheimers disease dementia. Amyloid positron emission tomography (PET) has been used for detecting Aβ deposition, but its high cost is a significant barrier for clinical usage. Therefore, we aimed to develop a new predictive scale for amyloid PET positivity using easily accessible tools. Overall, 161 aMCI patients were recruited from six memory clinics and underwent neuropsychological tests, brain magnetic resonance imaging (MRI), apolipoprotein E (

Hypothermia after Perinatal Asphyxia Does Not Affect Genes Responsible for Amyloid Production in Neonatal Peripheral Lymphocytes.

In this study, the expression of the genes of the

Diterpenoid Caesalmin C Delays Aβ-Induced Paralysis Symptoms via the DAF-16 Pathway in

Alzheimers disease (AD) is the most prevalent neurodegenerative disease in the world. However, there is no effective drug to cure it. Caesalmin C is a cassane-type diterpenoid abundant in

Microtube Array Membrane Encapsulated Cell Therapy A Novel Platform Technology Solution for Treatment of Alzheimers Disease.

Alzheimers disease is the most frequent form of dementia in aging population and is presently the worlds sixth largest cause of mortality. With the advancement of therapies, several solutions have been developed such as passive immunotherapy against these misfolded proteins, thereby resulting in the clearance. Within this segment, encapsulated cell therapy (ECT) solutions that utilize antibody releasing cells have been proposed with a multitude of techniques under development. Hence, in this study, we utilized our novel and patented Microtube Array Membranes (MTAMs) as an encapsulating platform system with anti-pTau antibody-secreting hybridoma cells to study the impact of it on Alzheimers disease. In vivo results revealed that in the water maze, the mice implanted with hybridoma cell MTAMs intracranially (IN) and subcutaneously (SC) showed improvement in the time spent the goal quadrant and escape latency. In passive avoidance, hybridoma cell loaded MTAMs (IN and SC) performed significantly well in step-through latency. At the end of treatment, animals with hybridoma cell loaded MTAMs had lower phosphorylated tau (pTau) expression than empty MTAMs had. Combining both experimental results unveiled that the clearance of phosphorylated tau might rescue the cognitive impairment associated with AD.

Recent Advances on the Role of Brain-Derived Neurotrophic Factor (BDNF) in Neurodegenerative Diseases.

Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are essential for neuronal survival and growth. The signaling cascades initiated by BDNF and its receptor are the key regulators of synaptic plasticity, which plays important role in learning and memory formation. Changes in BDNF levels and signaling pathways have been identified in several neurodegenerative diseases, including Alzheimers disease, Parkinsons disease, and Huntingtons disease, and have been linked with the symptoms and course of these diseases. This review summarizes the current understanding of the role of BDNF in several neurodegenerative diseases, as well as the underlying molecular mechanism. The therapeutic potential of BDNF treatment is also discussed, in the hope of discovering new avenues for the treatment of neurodegenerative diseases.

PARK7DJ-1 as a Therapeutic Target in Gut-Brain Axis Diseases.

It is increasingly known that Parkinsons (PD) and Alzheimers (AD) diseases occur more frequently in patients with inflammatory gastrointestinal diseases including inflammatory bowel (IBD) or celiac disease, indicating a pathological link between them. Although epidemiological observations suggest the existence of the gut-brain axis (GBA) involving systemic inflammatory and neural pathways, little is known about the exact molecular mechanisms. Parkinsons disease 7 (PARK7DJ-1) is a multifunctional protein whose protective role has been widely demonstrated in neurodegenerative diseases, including PD, AD, or ischemic stroke. Recent studies also revealed the importance of PARK7DJ-1 in the maintenance of the gut microbiome and also in the regulation of intestinal inflammation. All these findings suggest that PARK7DJ-1 may be a link and also a potential therapeutic target in gut and brain diseases. In this review, therefore, we discuss our current knowledge about PARK7DJ-1 in the context of GBA diseases.

Molecular Hydrogen Neuroprotection in Post-Ischemic Neurodegeneration in the Form of Alzheimers Disease Proteinopathy Underlying Mechanisms and Potential for Clinical Implementation-Fantasy or Reality

Currently, there is a lot of public interest in naturally occurring substances with medicinal properties that are minimally toxic, readily available and have an impact on health. Over the past decade, molecular hydrogen has gained the attention of both preclinical and clinical researchers. The death of pyramidal neurons in especially the CA1 area of the hippocampus, increased permeability of the blood-brain barrier, neuroinflammation, amyloid accumulation, tau protein dysfunction, brain atrophy, cognitive deficits and dementia are considered an integral part of the phenomena occurring during brain neurodegeneration after ischemia. This review focuses on assessing the current state of knowledge about the neuroprotective effects of molecular hydrogen following ischemic brain injury. Recent studies in animal models of focal or global cerebral ischemia and cerebral ischemia in humans suggest that hydrogen has pleiotropic neuroprotective properties. One potential mechanism explaining some of the general health benefits of using hydrogen is that it may prevent aging-related changes in cellular proteins such as amyloid and tau protein. We also present evidence that, following ischemia, hydrogen improves cognitive and neurological deficits and prevents or delays the onset of neurodegenerative changes in the brain. The available evidence suggests that molecular hydrogen has neuroprotective properties and may be a new therapeutic agent in the treatment of neurodegenerative diseases such as neurodegeneration following cerebral ischemia with progressive dementia. We also present the experimental and clinical evidence for the efficacy and safety of hydrogen use after cerebral ischemia. The therapeutic benefits of gas therapy open up new promising directions in breaking the translational barrier in the treatment of ischemic stroke.

Platelets and the Role of P2X Receptors in Nociception, Pain, Neuronal Toxicity and Thromboinflammation.

P2X receptors belong to a family of cation channel proteins, which respond to extracellular adenosine 5-triphosphate (ATP). These receptors have gained increasing attention in basic and translational research, as they are central to a variety of important pathophysiological processes such as the modulation of cardiovascular physiology, mediation of nociception, platelet and macrophage activation, or neuronal-glial integration. While P2X1 receptor activation is long known to drive platelet aggregation, P2X7 receptor antagonists have recently been reported to inhibit platelet activation. Considering the role of both P2X receptors and platelet-mediated inflammation in neuronal diseases such as multiple sclerosis, Alzheimers disease, Parkinsons disease, and stroke, targeting purinergic receptors may provide a valuable novel therapeutic approach in these diseases. Therefore, the present review illuminates the role of platelets and purinergic signaling in these neurological conditions to evaluate potential translational implications.

Use of PET Imaging to Assess the Efficacy of Thiethylperazine to Stimulate Cerebral MRP1 Transport Activity in Wild-Type and APPPS1-21 Mice.

Multidrug resistance-associated protein 1 (MRP1, encoded by the

Dysregulated Brain Protein Phosphorylation Linked to Increased Human Tau Expression in the hTau Transgenic Mouse Model.

Altered protein phosphorylation is a major pathologic modification in tauopathies and Alzheimers disease (AD) linked to abnormal tau fibrillar deposits in neurofibrillary tangles (NFTs) and pre-tangles and β-amyloid deposits in AD. hTau transgenic mice, which express 3R and less 4R human tau with no mutations in a murine knock-out background, show increased tau deposition in neurons but not NFTs and pre-tangles at the age of nine months. Label-free (phospho)proteomics and SWATH-MS identified 2065 proteins in hTau and wild-type (WT) mice. Only six proteins showed increased levels in hTau no proteins were down-regulated. Increased tau phosphorylation in hTau was detected at Ser199, Ser202, Ser214, Ser396, Ser400, Thr403, Ser404, Ser413, Ser416, Ser422, Ser491, and Ser494, in addition to Thr181, Thr231, Ser396Ser404, but not at Ser202Thr205. In addition, 4578 phosphopeptides (corresponding to 1622 phosphoproteins) were identified in hTau and WT mice 64 proteins were differentially phosphorylated in hTau. Sixty proteins were grouped into components of membranes, membrane signaling, synapses, vesicles, cytoskeleton, DNARNAprotein metabolism, ubiquitinproteasome system, cholesterol and lipid metabolism, and cell signaling. These results showed that over-expression of human tau without pre-tangle and NFT formation preferentially triggers an imbalance in the phosphorylation profile of specific proteins involved in the cytoskeletal-membrane-signaling axis.

In Vivo Dynamic Movement of Polymerized Amyloid β in the Perivascular Space of the Cerebral Cortex in Mice.

Disposition of amyloid β (Aβ) into the perivascular space of the cerebral cortex has been recently suggested as a major source of its clearance, and its disturbance may be involved in the pathogenesis of cerebral amyloid angiopathy and Alzheimers disease. Here, we explored the in vivo dynamics of Aβ in the perivascular space of anesthetized mice. Live images were obtained with two-photon microscopy through a closed cranial window. Either fluorescent-dye-labeled Aβ oligomers prepared freshly or Aβ fibrils after 6 days of incubation at 37 °C were placed over the cerebral cortex. Accumulation of Aβ was observed in the localized perivascular space of the penetrating arteries and veins. Transportation of the accumulated Aβ along the vessels was slow and associated with changes in shape. Aβ oligomers were transported smoothly and separately, whereas Aβ fibrils formed a mass and moved slowly. Parenchymal accumulation of Aβ oligomers, as well as Aβ fibrils along capillaries, increased gradually. In conclusion, we confirmed Aβ transportation between the cortical surface and the deeper parenchyma through the perivascular space that may be affected by the peptide polymerization. Facilitation of Aβ excretion through the system can be a key target in treating Alzheimers disease.

Biomarkers of Dementia with Lewy Bodies Differential Diagnostic with Alzheimers Disease.

Dementia with Lewy Bodies (DLB) is a common form of cognitive neurodegenerative disease. Only one third of patients are correctly diagnosed due to the clinical similarity mainly with Alzheimers disease (AD). In this review, we evaluate the interest of different biomarkers cerebrospinal fluid (CSF), brain MRI, FP-CIT SPECT, MIBG SPECT, PET by focusing more specifically on differential diagnosis between DLB and AD. FP-CIT SPECT is of high interest to discriminate DLB and AD, but not at the prodromal stage (i.e., MCI). MIBG SPECT with decreased cardiac sympathetic activity, perfusion SPECT with occipital hypoperfusion, FDG PET with occipital hypometabolism and cingulate island signs are of interest at the dementia stage but with a lower validity. Brain MRI has shown differences in group study with lower grey matter concentration of the Insula in prodromal DLB, but its interest in clinical routines is not demonstrated. Concerning CSF biomarkers, many studies have already examined the relevance of AD biomarkers but also alpha-synuclein assays in DLB, so we will focus as comprehensively as possible on other biomarkers (especially those that do not appear to be directly related to synucleinopathy) that may be of interest in the differential diagnosis between AD and DLB. Furthermore, we would like to highlight the growing interest in CSF synuclein RT-QuIC, which seems to be an excellent discrimination tool but its application in clinical routine remains to be demonstrated, given the non-automation of the process.

Cognition Impairment and Gait Disorders in Older Adults.

Thanks to the increase in life expectancy linked to scientific and medical progress and improvements in hygiene conditions, the population of people aged 75 years and over continues to grow worldwide, particularly in industrialized countries ....

Alzheimers Disease Association with Metals and Metalloids Concentration in Blood and Urine.

As there is some evidence that the risk for Alzheimers disease (AD) is partially attributable to environmental exposure to some metals and metalloids, we examined an association between AD and arsenic, chromium, and selenium in 53 AD patients and 217 controls. Urinary arsenic, blood chromium, and selenium were determined by inductively coupled plasma mass spectrometry. Logistic regression models calculating odds ratios (ORs) and 95% confidence intervals (CI) were used to estimate AD association with arsenic, chromium, and selenium. In AD patients, urinary arsenic and blood chromium were significantly higher, while blood selenium was significantly lower compared to controls. Increased blood selenium was related to a significant decrease in the odds of AD after adjustment for risk factors. Blood selenium per 1 kg × 10

The Effectiveness of Multi-Component Interventions on the Positive and Negative Aspects of Well-Being among Informal Caregivers of People with Dementia A Systematic Review and Meta-Analysis.

The present review aims to examine whether multi-component interventions for informal caregivers of people with dementia are effective on positive and negative aspects of caregiver well-being. Eleven databases were searched from inception to 8 March 2021. Only randomized controlled trials reporting the effectiveness of multi-component intervention on positive and negative aspects of caregiver well-being were eligible. Endnote X7 (Thomson ResearchSoft, Stanford, CA, USA) was used for study selection and version 5.1.0 of Cochrane Collaborations tool (Cochrane, London, UK) was applied for quality assessment. Review Manager (Revman) Version 5.3 (Cochrane, London, UK) was used for the meta-analysis, and if statistical synthesis was inappropriate, only narrative analysis was performed. A total of 31 RCTs with 3939 participants were included. Meta-analyses showed small to moderate effects on subjective well-being, depression, and burden of caregivers, and a moderate to high effect on caregiver anxiety. Due to insufficient data and vast heterogeneity, meta-analysis was not performed for other outcomes, such as resilience, competence, and empathy. This review suggests that individualized multi-component interventions for caregivers may be one of the ways to promote their well-being. Further research is needed to explore the impact of rigorously designed and personalized multi-component interventions on informal caregivers, especially on more positive indicators, as well as its long-term effects and sustainability.

Correction Lin et al. Grounding the Body Improves Sleep Quality in Patients with Mild Alzheimers Disease A Pilot Study.

The authors would like to make the following corrections to the published paper ....

Review of Active Extracorporeal Medical Devices to Counteract Freezing of Gait in Patients with Parkinson Disease.

Parkinson Disease (PD) primarily affects older adults. It is the second-most common neurodegenerative disease after Alzheimers disease. Currently, more than 10 million people suffer from PD, and this number is expected to grow, considering the increasing global longevity. Freezing of Gait (FoG) is a symptom present in approximately 80% of advanced-stage PDs patients. FoG episodes alter the continuity of gait, and may be the cause of falls that can lead to injuries and even death. The recent advances in the development of hardware and software systems for the monitoring, stimulus, or rehabilitation of patients with FoG has been of great interest to researchers because detection and minimization of the duration of FoG events is an important factor in improving the quality of life. This article presents a review of the research on non-invasive medical devices for FoG, focusing on the acquisition, processing, and stimulation approaches used.

Hibiscus, Rooibos, and Yerba Mate for Healthy Aging A Review on the Attenuation of In Vitro and In Vivo Markers Related to Oxidative Stress, Glycoxidation, and Neurodegeneration.

The world is currently undergoing a demographic change towards an increasing number of elderly citizens. Aging is characterized by a temporal decline in physiological capacity, and oxidative stress is a hallmark of aging and age-related disorders. Such an oxidative state is linked to a decrease in the effective mechanisms of cellular repair, the incidence of post-translational protein glycation, mitochondrial dysfunction, and neurodegeneration, just to name some of the markers contributing to the establishment of age-related reduction-oxidation, or redox, imbalance. Currently, there are no prescribed therapies to control oxidative stress however, there are strategies to elevate antioxidant defenses and overcome related health challenges based on the adoption of nutritional therapies. It is well known that herbal teas such, as hibiscus, rooibos, and yerba mate, are important sources of antioxidants, able to prevent some oxidation-related stresses. These plants produce several bioactive metabolites, have a pleasant taste, and a long-lasting history as safe foods. This paper reviews the literature on hibiscus, rooibos, and yerba mate teas in the context of nutritional strategies for the attenuation of oxidative stress-related glycoxidation and neurodegeneration, and, here, Alzheimers Disease is approached as an example. The focus is given to mechanisms of glycation inhibition, as well as neuroprotective in vitro effects, and, in animal studies, to frame interest in these plants as nutraceutical agents related to current health concerns.

Alzheimers Disease Connected Genes in the Post-Ischemic Hippocampus and Temporal Cortex.

It is considered that brain ischemia can be causative connected to Alzheimers disease. In the CA1 and CA3 regions of the hippocampus and temporal cortex, genes related to Alzheimers disease, such as the

Differentially Expressed miRNAs in Age-Related Neurodegenerative Diseases A Meta-Analysis.

To date, no neurodegenerative diseases (NDDs) have cures, and the underlying mechanism of their pathogenesis is undetermined. As miRNAs extensively regulate all biological processes and are crucial regulators of healthy brain function, miRNAs differentially expressed in NDDs may provide insight into the factors that contribute to the emergence of protein inclusions and the propagation of deleterious cellular environments. A meta-analysis of miRNAs dysregulated in Alzheimers disease, Parkinsons disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies and frontotemporal lobar degeneration (TDP43 variant) was performed to determine if diseases within a proteinopathy have distinct or shared mechanisms of action leading to neuronal death, and if proteinopathies can be classified on the basis of their miRNA profiles. Our results identified both miRNAs distinct to the anatomy, disease type and pathology, and miRNAs consistently dysregulated within single proteinopathies and across neurodegeneration in general. Our results also highlight the necessity to minimize the variability between studies. These findings showcase the need for more transcriptomic research on infrequently occurring NDDs, and the need for the standardization of research techniques and platforms utilized across labs and diseases.

Multisystem Proteinopathy Due to

In this work, we review clinical features and genetic diagnosis of diseases caused by mutations in the gene encoding valosin-containing protein (VCPp97), the functionally diverse AAA-ATPase. VCP is crucial to a multitude of cellular functions including protein quality control, stress granule formation and clearance, and genomic integrity functions, among others. Pathogenic mutations in

Assessment of Bidirectional Relationships between Leisure Sedentary Behaviors and Neuropsychiatric Disorders A Two-Sample Mendelian Randomization Study.

(1) Background Increasing evidence shows that sedentary behaviors are associated with neuropsychiatric disorders (NPDs) and thus may be a modifiable factor to target for the prevention of NPDs. However, the direction and causality for the relationship remain unknown sedentary behaviors could increase or decrease the risk of NPDs, andor NPDs may increase or decrease engagement in sedentary behaviors. (2) Methods This Mendelian randomization (MR) study with two samples included independent genetic variants related to sedentary behaviors (

The Prophylactic and Multimodal Activity of Two Isatin Thiosemicarbazones against Alzheimers Disease In Vitro.

Alzheimers disease (AD) is a multifactorial disorder strongly involving the formation of amyloid-β (Aβ) oligomers, which subsequently aggregate into the disease characteristic insoluble amyloid plaques, in addition to oxidative stress, inflammation and increased acetylcholinesterase activity. Moreover, Aβ oligomers interfere with the expression and activity of Glycogen synthase kinase-3 (GSK3) and Protein kinase B (PKB), also known as AKT. In the present study, the potential multimodal effect of two synthetic isatin thiosemicarbazones (ITSCs), which have been previously shown to prevent Aβ aggregation was evaluated. Both compounds resulted in fully reversing the Aβ-mediated toxicity in SK-NS-H cells treated with exogenous Aβ peptides at various pre-incubation time points and at 1 μM. Cell survival was not recovered when compounds were applied after Aβ cell treatment. The ITSCs were non-toxic against wild type and 5xFAD primary hippocampal cells. They reversed the inhibition of Akt and GSK-3β phosphorylation in 5xFAD cells. Finally, they exhibited good antioxidant potential and moderate lipoxygenase and acetylcholinesterase inhibition activity. Overall, these results suggest that isatin thiosemicarbazone is a suitable scaffold for the development of multimodal anti-AD agents.

A Brief Introduction to Magnetoencephalography (MEG) and Its Clinical Applications.

Magnetoencephalography (MEG) plays a pivotal role in the diagnosis of brain disorders. In this review, we have investigated potential MEG applications for analysing brain disorders. The signal-to-noise ratio (SNR

Targeting the Cation-Chloride Co-Transporter NKCC1 to Re-Establish GABAergic Inhibition and an Appropriate ExcitatoryInhibitory Balance in Selective Neuronal Circuits A Novel Approach for the Treatment of Alzheimers Disease.

GABA, the main inhibitory neurotransmitter in the adult brain, depolarizes and excites immature neurons because of an initially higher intracellular chloride concentration Cl

Ultrasound-Mediated Bioeffects in Senescent Mice and Alzheimers Mouse Models.

Ultrasound is routinely used for a wide range of diagnostic imaging applications. However, given that ultrasound can operate over a wide range of parameters that can all be modulated, its applicability extends far beyond the bioimaging field. In fact, the modality has emerged as a hybrid technology that effectively assists drug delivery by transiently opening the blood-brain barrier (BBB) when combined with intravenously injected microbubbles, and facilitates neuromodulation. Studies in aged mice contributed to an insight into how low-intensity ultrasound brings about its neuromodulatory effects, including increased synaptic plasticity and improved cognitive functions, with a potential role for neurogenesis and the modulation of NMDA receptor-mediated neuronal signalling. This work is complemented by studies in mouse models of Alzheimers disease (AD), a form of pathological ageing. Here, ultrasound was mainly employed as a BBB-opening tool that clears protein aggregates via microglial activation and neuronal autophagy, thereby restoring cognition. We discuss the currently available ultrasound approaches and how studies in senescent mice are relevant for AD and can accelerate the application of low-intensity ultrasound in the clinic.

Homology Modelling, Molecular Docking and Molecular Dynamics Simulation Studies of CALMH1 against Secondary Metabolites of

Calcium homeostasis modulator 1 (CALHM1) is a protein responsible for causing Alzheimers disease. In the absence of an experimentally designed protein molecule, homology modelling was performed. Through homology modelling, different CALHM1 models were generated and validated through Rampage. To carry out further in silico studies, through molecular docking and molecular dynamics simulation experiments, various flavonoids and alkaloids from

Shen Qi Wan Ameliorates Learning and Memory Impairment Induced by STZ in AD Rats through PI3KAKT Pathway.

Alzheimers disease is the most common form of neurodegenerative disease, and increasing evidence shows that insulin signaling has crucial roles in AD initiation and progression. In this study, we explored the effect and underlying mechanism of SQW, a representative formula for tonifying the kidney and promoting yang, on improving the cognitive function in a streptozotocin-induced model of AD rats. We investigated memory impairment in the AD rats by using the Morris water test. HE and Nissl staining were employed to observe the histomorphological changes in the hippocampal. Expression levels of NeuN and proteins related to Tau and apoptosis were measured using immunohistochemistry and Western blotting, respectively. Additionally, we performed RNA sequencing, and the selected hub genes were then validated by qRT-PCR. Furthermore, the protein expression levels of PI3KAKT pathway-related proteins were detected by Western blot. We found that SQW treatment significantly alleviated learning and memory impairment, pathological damage, and apoptosis in rats, as evidenced by an increased level of NeuN and Bcl-2, and decreased phosphorylation of Tau, Bax, and Caspase-3 protein expression. SQW treatment reversed the expression of insulin resistance-related genes (Nr4a1, Lpar1, Bdnf, Atf2, and Ppp2r2b) and reduced the inhibition of the PI3KAKT pathway. Our results demonstrate that SQW could contribute to neuroprotection against learning and memory impairment in rats induced by STZ through activation of the PI3KAKT pathway.

Flavonoid Derivatives as Potential Cholinesterase Inhibitors in Scopolamine-Induced Amnesic Mice An In Vitro, In Vivo and Integrated Computational Approach.

Flavonoids are one of the most exciting types of phenolic compounds with a wide range of bioactive benefits. A series of flavone derivatives (

Lower Posterior Cingulate N-Acetylaspartate to Creatine Level in Early Detection of Biologically Defined Alzheimers Disease.

Alzheimers disease (AD) was recently defined as a biological construct to reflect neuropathologic status, and both abnormal amyloid and tau are required for a diagnosis of AD. We aimed to determine the proton MR spectroscopic (

Correlations between Persistent Olfactory and Semantic Memory Disorders after SARS-CoV-2 Infection.

A Quantitative Proteomic Approach Explores the Possible Mechanisms by Which the Small Molecule Stemazole Promotes the Survival of Human Neural Stem Cells.

Neurodegenerative disorders have become a serious healthcare problem worldwide and there is no efficacious cure. However, regulating the fate of stem cells is an effective way to treat these neurological diseases. In previous work, stemazole was reported to maintain the survival of human neural stem cells in the absence of growth factors and to have therapeutic effects on neurodegenerative diseases. However, although it is a promising small molecule, the molecular mechanisms against apoptosis are ambiguous. In this study, tandem mass tag (TMT)-based proteomics were performed to obtain whole protein expression profiles of human neural stem cells in different groups under extreme conditions. Bioinformatics analysis based on protein-protein interaction (PPI) network construction, gene ontology (GO) and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis were adopted to explore crucial proteins and possible pharmacological mechanisms. A total of 77 differentially expressed proteins were identified, comprising 38 upregulated proteins and 39 downregulated proteins. Combined with a diseases database of Alzheimers disease (AD), caspase-2 (CASP2), PKA C-alpha (PRKACA), fibronectin (FN1), large neutral amino acid transporter small subunit 1 (SLC7A5), which are involved in cell proliferation and apoptosis, this was further validated by enzyme activity assay and molecular docking, and regarded as putative targets regulated by stemazole. The present results give an insight into this small molecule and a better understanding for further elucidating the underlying mechanisms in the treatment of stem cells and neurodegenerative diseases.

Insulin and Its Key Role for Mitochondrial FunctionDysfunction and Quality Control A Shared Link between Dysmetabolism and Neurodegeneration.

Insulin was discovered and isolated from the beta cells of pancreatic islets of dogs and is associated with the regulation of peripheral glucose homeostasis. Insulin produced in the brain is related to synaptic plasticity and memory. Defective insulin signaling plays a role in brain dysfunction, such as neurodegenerative disease. Growing evidence suggests a link between metabolic disorders, such as diabetes and obesity, and neurodegenerative diseases, especially Alzheimers disease (AD). This association is due to a common state of insulin resistance (IR) and mitochondrial dysfunction. This review takes a journey into the past to summarize what was known about the physiological and pathological role of insulin in peripheral tissues and the brain. Then, it will land in the present to analyze the insulin role on mitochondrial health and the effects on insulin resistance and neurodegenerative diseases that are IR-dependent. Specifically, we will focus our attention on the quality control of mitochondria (MQC), such as mitochondrial dynamics, mitochondrial biogenesis, and selective autophagy (mitophagy), in healthy and altered cases. Finally, this review will be projected toward the future by examining the most promising treatments that target the mitochondria to cure neurodegenerative diseases associated with metabolic disorders.

Enhanced Anxiety and Olfactory Microglial Activation in Early-Stage Familial Alzheimers Disease Mouse Model.

Anxiety is a known comorbidity and risk factor for conversion to neuroinflammation-mediated dementia in patients with Alzheimers disease (AD). Here, we investigated if anxiety occurred as an early endophenotype of mutant familial AD (5 × FAD) male mice and the underlying neuroinflammatory mechanisms. We observed that compared to wildtype (WT) littermates, 5 × FAD mice showed enhanced anxiety at as early as 2 months old (mo). Interestingly, these 5 × FAD male mice had concomitantly increased mRNA levels of pro-inflammatory cytokines such as interleukin 1 beta (

Patterns of Focal Amyloid Deposition Using

Accumulation of aggregated amyloid-β (Aβ) in the brain is considered the first pathological event within the pathogenesis of Alzheimers disease (AD). It is difficult to accurately identify the initial brain regions of Aβ accumulation due to the time-lag between the start of the pathophysiology and symptom onset. However, focal regional amyloid uptake on amyloid PET scans may provide insights into this. Hence, we aimed to evaluate the topographic distribution of amyloid deposition in patients with cognitive impairment and to identify the starting order of amyloid accumulation in the brain using conditional probability. We enrolled 58 patients composed of 9 normal cognition (NC), 32 mild cognitive impairment (MCI), and 17 dementia showing focal regional amyloid deposition corresponding to a brain amyloid plaque load (BAPL) score of 2 among those who visited the Memory Clinic of Asan Medical Center and underwent an

Dysregulated Ca

Calcium ions (Ca

Examples of Inverse Comorbidity between Cancer and Neurodegenerative Diseases A Possible Role for Noncoding RNA.

Cancer is one of the most common causes of death in parallel, the incidence and prevalence of central nervous system diseases are equally high. Among neurodegenerative diseases, Alzheimers dementia is the most common, while Parkinsons disease (PD) is the second most frequent neurodegenerative disease. There is a significant amount of evidence on the complex biological connection between cancer and neurodegeneration. Noncoding RNAs (ncRNAs) are defined as transcribed nucleotides that perform a variety of regulatory functions. The mechanisms by which ncRNAs exert their functions are numerous and involve every aspect of cellular life. The same ncRNA can act in multiple ways, leading to different outcomes in fact, a single ncRNA can participate in the pathogenesis of more than one disease-even if these seem very different, as cancer and neurodegenerative disorders are. The ncRNA activates specific pathways leading to one or the other clinical phenotype, sometimes with obvious mechanisms of inverse comorbidity. We aimed to collect from the existing literature examples of inverse comorbidity in which ncRNAs seem to play a key role. We also investigated the example of mir-519a-3p, and one of its target genes Poly (ADP-ribose) polymerase 1, for the inverse comorbidity mechanism between some cancers and PD. We believe it is very important to study the inverse comorbidity relationship between cancer and neurodegenerative diseases because it will help us to better assess these two major areas of human disease.

New Insights into Neuroinflammation Involved in Pathogenic Mechanism of Alzheimers Disease and Its Potential for Therapeutic Intervention.

Alzheimers disease (AD) is the most common form of dementia, affecting more than 50 million people worldwide with an estimated increase to 139 million people by 2050. The exact pathogenic mechanisms of AD remain elusive, resulting in the fact that the current therapeutics solely focus on symptomatic management instead of preventative or curative strategies. The two most widely accepted pathogenic mechanisms of AD include the amyloid and tau hypotheses. However, it is evident that these hypotheses cannot fully explain neuronal degeneration shown in AD. Substantial evidence is growing for the vital role of neuroinflammation in AD pathology. The neuroinflammatory hypothesis provides a new, exciting lead in uncovering the underlying mechanisms contributing to AD. This review aims to highlight new insights into the role of neuroinflammation in the pathogenesis of AD, mainly including the involvement of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3)caspase-1 axis, triggering receptor expressed on myeloid cells 2 (TREM2) and cGAS-STING as key influencers in augmenting AD development. The inflammasomes related to the pathways of NF-κB, NLRP3, TREM2, and cGAS-STING as biomarkers of the neuroinflammation associated with AD, as well as an overview of novel AD treatments based on these biomarkers as potential drug targets reported in the literature or under clinical trials, are explored.

Innate Immune Cell Death in Neuroinflammation and Alzheimers Disease.

Alzheimers disease (AD) is a neurodegenerative disorder molecularly characterized by the formation of amyloid β (Aβ) plaques and type 2 microtubule-associated protein (Tau) abnormalities. Multiple studies have shown that many of the brains immunological cells, specifically microglia and astrocytes, are involved in AD pathogenesis. Cells of the innate immune system play an essential role in eliminating pathogens but also regulate brain homeostasis and AD. When activated, innate immune cells can cause programmed cell death through multiple pathways, including pyroptosis, apoptosis, necroptosis, and PANoptosis. The cell death often results in the release of proinflammatory cytokines that propagate the innate immune response and can eliminate Aβ plaques and aggregated Tau proteins. However, chronic neuroinflammation, which can result from cell death, has been linked to neurodegenerative diseases and can worsen AD. Therefore, the innate immune response must be tightly balanced to appropriately clear these AD-related structural abnormalities without inducing chronic neuroinflammation. In this review, we discuss neuroinflammation, innate immune responses, inflammatory cell death pathways, and cytokine secretion as they relate to AD. Therapeutic strategies targeting these innate immune cell death mechanisms will be critical to consider for future preventive or palliative treatments for AD.

MicroRNA Networks in Cognition and Dementia.

The change from viewing noncoding RNA as junk in the genome to seeing it as a critical epigenetic regulator in almost every human condition or disease has forced a paradigm shift in biomedical and clinical research. Small and long noncoding RNA transcripts are now routinely evaluated as putative diagnostic or therapeutic agents. A prominent role for noncoding microRNAs in the central nervous system has uncovered promising new clinical candidates for dementia-related disorders, treatments for which currently remain elusive even as the percentage of diagnosed patients increases significantly. Cognitive decline is a core neurodegenerative process in Alzheimers Disease, Frontotemporal Dementia, Lewy body dementia, vascular dementia, Huntingtons Disease, Creutzfeldt-Jakob disease, and a significant portion of Parkinsons Disease patients. This review will discuss the microRNA-associated networks which influence these pathologies, including inflammatory and viral-mediated pathways (such as the novel

Neuronal Rubicon Represses Extracellular APPAmyloid β Deposition in Alzheimers Disease.

Alzheimers disease (AD) is the most prevalent age-associated neurodegenerative disease. A decrease in autophagy during aging contributes to brain disorders by accumulating potentially toxic substrates in neurons. Rubicon is a well-established inhibitor of autophagy in all cells. However, Rubicon participates in different pathways depending on cell type, and little information is currently available on neuronal Rubicons role in the AD context. Here, we investigated the cell-specific expression of Rubicon in postmortem brain samples from AD patients and 5xFAD mice and its impact on amyloid β burden in vivo and neuroblastoma cells. Further, we assessed Rubicon levels in human-induced pluripotent stem cells (hiPSCs), derived from early-to-moderate AD and in postmortem samples from severe AD patients. We found increased Rubicon levels in AD-hiPSCs and postmortem samples and a notable Rubicon localization in neurons. In AD transgenic mice lacking Rubicon, we observed intensified amyloid β burden in the hippocampus and decreased Pacer and p62 levels. In APP-expressing neuroblastoma cells, increased APPamyloid β secretion in the medium was found when Rubicon was absent, which was not observed in cells depleted of Atg5, essential for autophagy, or Rab27a, required for exosome secretion. Our results propose an uncharacterized role of Rubicon on APPamyloid β homeostasis, in which neuronal Rubicon is a repressor of APPamyloid β secretion, defining a new way to target AD and other similar diseases therapeutically.

Biochemical Properties and Physiological Functions of pLG72 Twenty Years of Investigations.

In 2002, the novel human gene G72 was associated with schizophrenia susceptibility. This gene encodes a small protein of 153 amino acids, named pLG72, which represents a rare case of primate-specific protein. In particular, the rs2391191 single nucleotide polymorphism (resulting in in the R30K substitution) was robustly associated to schizophrenia and bipolar disorder. In this review, we aim to summarize the results of 20 years of biochemical investigations on pLG72. The main known role of pLG72 is related to its ability to bind and inactivate the flavoenzyme d-amino acid oxidase, i.e., the enzyme that controls the catabolism of d-serine, the main NMDA receptor coagonist in the brain. pLG72 was proposed to target the cytosolic form of d-amino acid oxidase for degradation, preserving d-serine and protecting the cell from oxidative stress generated by hydrogen peroxide produced by the flavoenzyme reaction. Anyway, pLG72 seems to play additional roles, such as affecting mitochondrial functions. The level of pLG72 in the human body is still a controversial issue because of its low expression and challenging detection. Anyway, the intriguing hypothesis that pLG72 level in blood could represent a suitable marker of Alzheimers disease progression (a suggestion not sufficiently established yet) merits further investigations.

Zinc in Regulating Protein Kinases and Phosphatases in Neurodegenerative Diseases.

Zinc is essential for human growth and development. As a trace nutrient, zinc plays important roles in numerous signal transduction pathways involved in distinct physiologic or pathologic processes. Protein phosphorylation is a posttranslational modification which regulates protein activity, degradation, and interaction with other molecules. Protein kinases (PKs) and phosphatases (PPs), with their effects of adding phosphate to or removing phosphate from certain substrates, are master regulators in controlling the phosphorylation of proteins. In this review, we summarize the disturbance of zinc homeostasis and role of zinc disturbance in regulating protein kinases and protein phosphatases in neurodegenerative diseases, with the focus of that in Alzheimers disease, providing a new perspective for understanding the mechanisms of these neurologic diseases.

DYRK1A and Activity-Dependent Neuroprotective Protein Comparative Diagnosis Interest in Cerebrospinal Fluid and Plasma in the Context of Alzheimer-Related Cognitive Impairment in Down Syndrome Patients.

Down syndrome (DS) is a complex genetic condition due to an additional copy of human chromosome 21, which results in the deregulation of many genes. In addition to the intellectual disability associated with DS, adults with DS also have an ultrahigh risk of developing early onset Alzheimers disease dementia. DYRK1A, a proline-directed serinethreonine kinase, whose gene is located on chromosome 21, has recently emerged as a promising plasma biomarker in patients with sporadic Alzheimers disease (AD). The protein DYRK1A is truncated in symptomatic AD, the increased truncated form being associated with a decrease in the level of full-length form. Activity-dependent neuroprotective protein (ADNP), a key protein for the brain development, has been demonstrated to be a useful marker for symptomatic AD and disease progression. In this study, we evaluated DYRK1A and ADNP in CSF and plasma of adults with DS and explored the relationship between these proteins. We used mice models to evaluate the effect of DYRK1A overexpression on ADNP levels and then performed a dual-center cross-sectional human study in adults with DS in Barcelona (Spain) and Paris (France). Both cohorts included adults with DS at different stages of the continuum of AD asymptomatic AD (aDS), prodromal AD (pDS), and AD dementia (dDS). Non-trisomic controls and patients with sporadic AD dementia were included for comparison. Full-form levels of DYRK1A were decreased in plasma and CSF in adults with DS and symptomatic AD (pDS and dDS) compared to aDS, and in patients with sporadic AD compared to controls. On the contrary, the truncated form of DYRK1A was found to increase both in CSF and plasma in adults with DS and symptomatic AD and in patients with sporadic AD with respect to aDS and controls. ADNP levels showed a more complex structure. ADNP levels increased in aDS groups vs. controls, in agreement with the increase in levels found in the brains of mice overexpressing DYRK1A. However, symptomatic individuals had lower levels than aDS individuals. Our results show that the comparison between full-length and truncated-form levels of DYRK1A coupled with ADNP levels could be used in trials targeting pathophysiological mechanisms of dementia in individuals with DS.

ROCK and PDE-5 Inhibitors for the Treatment of Dementia Literature Review and Meta-Analysis.

Dementia is a disease in which memory, thought, and behavior-related disorders progress gradually due to brain damage caused by injury or disease. It is mainly caused by Alzheimers disease or vascular dementia and several other risk factors, including genetic factors. It is difficult to treat as its incidence continues to increase worldwide. Many studies have been performed concerning the treatment of this condition. Rho-associated kinase (ROCK) and phosphodiesterase-5 (PDE-5) are attracting attention as pharmacological treatments to improve the symptoms. This review discusses how ROCK and PDE-5 affect Alzheimers disease, vascular restructuring, and exacerbation of neuroinflammation, and how their inhibition helps improve cognitive function. In addition, the results of the animal behavior analysis experiments utilizing the Morris water maze were compared through meta-analysis to analyze the effects of ROCK inhibitors and PDE-5 inhibitors on cognitive function. According to the selection criteria, 997 publications on ROCK and 1772 publications on PDE-5 were screened, and conclusions were drawn through meta-analysis. Both inhibitors showed good improvement in cognitive function tests, and what is expected of the synergy effect of the two drugs was confirmed in this review.

Systemic Inflammation Predicts Alzheimer Pathology in Community Samples without Dementia.

Neuroinflammation and oxidative stress (OS) are implicated in the pathophysiology of Alzheimers disease (AD). However, it is unclear at what stage of the disease process inflammation first becomes manifest. The aim of this study was to investigate the associations between specific plasma markers of inflammation and OS, tau, and Amyloid-β 38, 40, and 42 levels in cognitively unimpaired middle-age and older individuals. Associations between inflammatory states identified through principal component analysis and AD biomarkers were investigated in middle-age (52-56 years,

Co-Ultramicronized PalmitoylethanolamideLuteolin Restores Oligodendrocyte Homeostasis via Peroxisome Proliferator-Activated Receptor-α in an In Vitro Model of Alzheimers Disease.

Oligodendrocytes are cells fundamental for brain functions as they form the myelin sheath and feed axons. They perform these critical functions thanks to the cooperation with other glial cells, mainly astrocytes. The astrocyteoligodendrocyte crosstalk needs numerous mediators and receptors, such as peroxisome proliferator-activated receptors (PPARs). PPAR agonists promote oligodendrocyte precursor cells (OPCs) maturation in myelinating oligodendrocytes. In the Alzheimers disease brain, deposition of beta-amyloid (Aβ) has been linked to several alterations, including astrogliosis and changes in OPCs maturation. However, very little is known about the molecular mechanisms. Here, we investigated for the first time the maturation of OPCs co-cultured with astrocytes in an in vitro model of Aβ

Antimicrobial Peptides (AMPs) in the Pathogenesis of Alzheimers Disease Implications for Diagnosis and Treatment.

Alzheimers 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 (Aβ) 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. The literature also demonstrates that Aβ can be considered itself as an AMP thus, representing a type of innate immune defense peptide that protects the host against a variety of pathogens. Beyond Aβ, 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 summarized and discussed these findings and explored the diagnostic and therapeutic potential of AMPs in AD.

Biochemical Discrimination of the Down Syndrome-Related Metabolic and OxidativeNitrosative Stress Alterations from the Physiologic Age-Related Changes through the Targeted Metabolomic Analysis of Serum.

Down Syndrome (DS) is a neurodevelopmental disorder that is characterized by an accelerated aging process, frequently associated with the development of Alzheimers disease (AD). Previous studies evidenced that DS patients have various metabolic anomalies, easily measurable in their serum samples, although values that were found in DS patients were compared with those of age-matched non-DS patients, thus hampering to discriminate the physiologic age-related changes of serum metabolites from those that are truly caused by the pathologic processes associated with DS. In the present study we performed a targeted metabolomic evaluation of serum samples from DS patients without dementia of two age classes (Younger DS Patients, YDSP, aging 20-40 years Aged DS Patients, ADSP, aging 41-60 years), comparing the results with those that were obtained in two age classes of non-DS patients (Younger non-DS Patients, YnonDSP, aging 30-60 years Aged-nonDS Patients, AnonDSP, aging 75-90 years). Of the 36 compounds assayed, 30 had significantly different concentrations in Pooled non-DS Patients (PnonDSP), compared to Pooled DS Patients (PDSP). Age categorization revealed that 1130 compounds were significantly different in AnonDSP, compared to YnonDSP, indicating physiologic, age-related changes of their circulating concentrations. A comparison between YDSP and ADSP showed that 1930 metabolites had significantly different values from those found in the corresponding classes of non-DS patients, strongly suggesting pathologic, DS-associated alterations of their serum levels. Twelve compounds selectively and specifically discriminated PnonDSP from PDSP, whilst only three discriminated YDSP from ADSP. The results allowed to determine, for the first time and to the best of our knowledge, the true, age-independent alterations of metabolism that are measurable in serum and attributable only to DS. These findings may be of high relevance for better strategies (pharmacological, nutritional) aiming to specifically target the dysmetabolism and decreased antioxidant defenses that are associated with DS.

Multi-Target Effects of ß-Caryophyllene and Carnosic Acid at the Crossroads of Mitochondrial Dysfunction and Neurodegeneration From Oxidative Stress to Microglia-Mediated Neuroinflammation.

Inflammation and oxidative stress are interlinked and interdependent processes involved in many chronic diseases, including neurodegeneration, diabetes, cardiovascular diseases, and cancer. Therefore, targeting inflammatory pathways may represent a potential therapeutic strategy. Emerging evidence indicates that many phytochemicals extracted from edible plants have the potential to ameliorate the disease phenotypes. In this scenario, ß-caryophyllene (BCP), a bicyclic sesquiterpene, and carnosic acid (CA), an ortho-diphenolic diterpene, were demonstrated to exhibit anti-inflammatory, and antioxidant activities, as well as neuroprotective and mitoprotective effects in different in vitro and in vivo models. BCP essentially promotes its effects by acting as a selective agonist and allosteric modulator of cannabinoid type-2 receptor (CB2R). CA is a pro-electrophilic compound that, in response to oxidation, is converted to its electrophilic form. This can interact and activate the Keap1Nrf2ARE transcription pathway, triggering the synthesis of endogenous antioxidant phase 2 enzymes. However, given the nature of its chemical structure, CA also exhibits direct antioxidant effects. BCP and CA can readily cross the BBB and accumulate in brain regions, giving rise to neuroprotective effects by preventing mitochondrial dysfunction and inhibiting activated microglia, substantially through the activation of pro-survival signalling pathways, including regulation of apoptosis and autophagy, and molecular mechanisms related to mitochondrial quality control. Findings from different in vitroin vivo experimental models of Parkinsons disease and Alzheimers disease reported the beneficial effects of both compounds, suggesting that their use in treatments may be a promising strategy in the management of neurodegenerative diseases aimed at maintaining mitochondrial homeostasis and ameliorating glia-mediated neuroinflammation.

Bioenergetic and Autophagic Characterization of Skin Fibroblasts from

The objective of this study is to describe the alterations occurring during the neurodegenerative process in skin fibroblast cultures from

Dipeptide of ψ-GSH Inhibits Oxidative Stress and Neuroinflammation in an Alzheimers Disease Mouse Model.

Supplementation of glutathione (GSH) levels through varying formulations or precursors has thus far appeared to be a tenable strategy to ameliorate disease-associated oxidative stress. Metabolic liability of GSH and its precursors, i.e., hydrolysis by the ubiquitous γ-glutamyl transpeptidase (γ-GT), has limited successful clinical translation due to poor bioavailability. We addressed this problem through the design of γ-GT-resistant GSH analogue, ψ-GSH, which successfully substituted in GSH-dependent enzymatic systems and also offered promise as a therapeutic for Alzheimers disease (AD). With the aim to improve its bioavailability, we studied the utility of a ψ-GSH precursor, dipeptide

Cognitive profile in mild cognitive impairment with Lewy bodies.

This study aimed to elucidate the cognitive profile of patients with mild cognitive impairment with Lewy bodies (MCI-LB) and to compare it to that of patients with mild cognitive impairment due to Alzheimers disease (MCI-AD). Subjects older than 60 years with probable MCI-LB (n 60) or MCI-AD (n 60) were recruited. All patients were tested with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) to assess their global cognitive profile. The MCI-AD and MCI-LB patients did not differ in total MMSE and MoCA scores. However, some sub-items in MMSE and MoCA were shown to be screening markers for differentiating MCI-LB from MCI-AD. In the visuoconstructive test, the total score and hands subitem score in the clock-drawing test were significantly lower in MCI-LB than in MCI-AD. As for the executive function, the animal fluency test, repeat digits backward test and take paper by your right hand in MMSE all showed lower scores in MCI-LB compared with MCI-AD. As for memory, velvet and church in MoCA and ball and national flag in MMSE had lower scores in MCI-AD than in MCI-LB. This study presents the cognitive profile of patients with MCI-LB. In line with the literature on Dementia with Lewy bodies, our results showed lower performance on tests for visuoconstructive and executive function, whereas memory remained relatively spared in the early period.

Fully automated and highly specific plasma β-amyloid immunoassays predict β-amyloid status defined by amyloid positron emission tomography with high accuracy.

Clinicians, researchers, and patients alike would greatly benefit from more accessible and inexpensive biomarkers for neural β-amyloid (Aβ). We aimed to assess the performance of fully automated plasma Aβ immunoassays, which correlate significantly with immunoprecipitation mass spectrometry assays, in predicting brain Aβ status as determined by visual read assessment of amyloid positron emission tomography (PET). The plasma Aβ42Aβ40 ratio was measured using a fully automated immunoassay platform (HISCL series) in two clinical studies (discovery and validation studies). The discovery and validation sample sets were retrospectively and randomly selected from participants with early Alzheimers disease (AD) identified during screening for the elenbecestat Phase 3 program. We included 197 participants in the discovery study (mean SD age 71.1 8.5 years 112 females) and 200 in the validation study (age 70.8 7.9 years 99 females). The plasma Aβ42Aβ40 ratio predicted amyloid PET visual read status with areas under the receiver operating characteristic curves of 0.941 (95% confidence interval CI 0.910-0.973) and 0.868 (95% CI 0.816-0.920) in the discovery and validation studies, respectively. In the discovery study, a cutoff value of 0.102 was determined based on maximizing the Youden Index, and the sensitivity and specificity were calculated to be 96.0% (95% CI 90.1-98.9%) and 83.5% (95% CI 74.6-90.3%), respectively. Using the same cutoff value, the sensitivity and specificity in the validation study were calculated to be 88.0% (95% CI 80.0-93.6%) and 72.0% (95% CI 62.1-80.5%), respectively. The plasma Aβ42Aβ40 ratio measured using the HISCL series achieved high accuracy in predicting amyloid PET status. Since our blood-based immunoassay system is less invasive and more accessible than amyloid PET and cerebrospinal fluid testing, it may contribute to the diagnosis of AD in routine clinical practice.

Pathological and neurophysiological outcomes of seeding human-derived tau pathology in the APP-KI NL-G-F and NL-NL mouse models of Alzheimers Disease.

The two main histopathological hallmarks that characterize Alzheimers Disease are the presence of amyloid plaques and neurofibrillary tangles. One of the current approaches to studying the consequences of amyloid pathology relies on the usage of transgenic animal models that incorporate the mutant humanized form of the amyloid precursor protein (hAPP), with animal models progressively developing amyloid pathology as they age. However, these mice models generally overexpress the hAPP protein to facilitate the development of amyloid pathology, which has been suggested to elicit pathological and neuropathological changes unrelated to amyloid pathology. In this current study, we characterized APP knock-in (APP-KI) animals, that do not overexpress hAPP but still develop amyloid pathology to understand the influence of protein overexpression. We also induced tau pathology via human-derived tau seeding material to understand the neurophysiological effects of amyloid and tau pathology. We report that tau-seeded APP-KI animals progressively develop tau pathology, exacerbated by the presence of amyloid pathology. Interestingly, older amyloid-bearing, tau-seeded animals exhibited more amyloid pathology in the entorhinal area, isocortex and hippocampus, but not thalamus, which appeared to correlate with impairments in gamma oscillations before seeding. Tau-seeded animals also featured immediate deficits in power spectra values and phase-amplitude indices in the hippocampus after seeding, with gamma power spectra deficits persisting in younger animals. Both deficits in hippocampal phase-amplitude coupling and gamma power differentiate tau-seeded, amyloid-positive animals from buffer controls. Based on our results, impairments in gamma oscillations appear to be strongly associated with the presence and development of amyloid and tau pathology, and may also be an indicator of neuropathology, network dysfunction, and even potential disposition to the future development of amyloid pathology.

Association of β-cell function and cognitive impairment in patients with abnormal glucose metabolism.

Insulin has been demonstrated to play an important role in the occurrence and development of Alzheimers disease, especially in those with diabetes. β cells are important insulin-producing cells in human pancreas. This study aimed to investigate the association between β-cell dysfunction and cognitive impairment among patients over 40-year-old with abnormal glucose metabolism in Chinese rural communities. A sample of 592 participants aged 40 years or older from the China National Stroke Prevention Project (CSPP) between 2015 and 2017 were enrolled in this study. Abnormal glucose metabolism was defined when hemoglobin Alc ≥ 5.7%. Cognitive function was assessed by the Beijing edition of the Montreal Cognitive Assessment scale. Homeostasis assessment of β-cell function was performed and classified into 4 groups according to the quartiles. A lower value of HOMA-β indicated a worse condition of β-cell function. Multivariate logistic regression was used to analyze the association between β-cell function and cognitive impairment. In a total of 592 patients with abnormal glucose metabolism, the average age was 60.20 ± 7.63 years and 60.1% patients had cognitive impairment. After adjusting for all potential risk factors, we found the first quartile of β-cell function was significantly associated with cognitive impairment (OR 2.27, 95%CI 1.32-3.92), especially at the domains of language (OR 1.64, 95%CI 1.01-2.65) and abstraction (OR 2.29, 95%CI 1.46-3.58). Our study showed that worse β-cell function is associated with cognitive impairment of people over 40-year-old with abnormal glucose metabolism in Chinese rural communities, especially in the cognitive domains of abstraction and language.

P. edulis Extract Protects Against Amyloid-β Toxicity in Alzheimers Disease Models Through Maintenance of Mitochondrial Homeostasis via the FOXO3DAF-16 Pathway.

Alzheimers disease (AD) is a common and devastating disease characterized by pathological aggregations of beta-amyloid (Aβ) plaques extracellularly, and Tau tangles intracellularly. While our understandings of the aetiologies of AD have greatly expanded over the decades, there is no drug available to stop disease progression. Here, we demonstrate the potential of Passiflora edulis (P. edulis) pericarp extract in protecting against Aβ-mediated neurotoxicity in mammalian cells and Caenorhabditis elegans (C. elegans) models of AD. We show P. edulis pericarp protects against memory deficit and neuronal loss, and promotes longevity in the Aβ model of AD via stimulation of mitophagy, a selective cellular clearance of damaged and dysfunctional mitochondria. P. edulis pericarp also restores memory and increases neuronal resilience in a C. elegans Tau model of AD. While defective mitophagy-induced accumulation of damaged mitochondria contributes to AD progression, P. edulis pericarp improves mitochondrial quality and homeostasis through BNIP3DCT1-dependent mitophagy and SOD-3-dependent mitochondrial resilience, both via increased nuclear translocation of the upstream transcriptional regulator FOXO3DAF-16. Further studies to identify active molecules in P. edulis pericarp that could maintain neuronal mitochondrial homeostasis may enable the development of potential drug candidates for AD.

Mnemonic construction and representation of temporal structure in the hippocampal formation.

The hippocampal-entorhinal region supports memory for episodic details, such as temporal relations of sequential events, and mnemonic constructions combining experiences for inferential reasoning. However, it is unclear whether hippocampal event memories reflect temporal relations derived from mnemonic constructions, event order, or elapsing time, and whether these sequence representations generalize temporal relations across similar sequences. Here, participants mnemonically constructed times of events from multiple sequences using infrequent cues and their experience of passing time. After learning, event representations in the anterior hippocampus reflected temporal relations based on constructed times. Temporal relations were generalized across sequences, revealing distinct representational formats for events from the same or different sequences. Structural knowledge about time patterns, abstracted from different sequences, biased the construction of specific event times. These findings demonstrate that mnemonic construction and the generalization of relational knowledge combine in the hippocampus, consistent with the simulation of scenarios from episodic details and structural knowledge.

Decision tree-based classification as a support to diagnosis in the Alzheimers disease continuum using cerebrospinal fluid biomarkers insights from automated analysis.

Cerebrospinal fluid (CSF) biomarkers add accuracy to the diagnostic workup of cognitive impairment by illustrating Alzheimers disease (AD) pathology. However, there are no universally accepted cutoff values for the interpretation of AD biomarkers. The aim of this study is to determine the viability of a decision-tree method to analyse CSF biomarkers of AD as a support for clinical diagnosis. A decision-tree method (automated classification analysis) was applied to concentrations of AD biomarkers in CSF as a support for clinical diagnosis in older adults with or without cognitive impairment in a Brazilian cohort. In brief, 272 older adults (68 with AD, 122 with mild cognitive impairment MCI, and 82 healthy controls) were assessed for CSF concentrations of Aß1-42, total-tau, and phosphorylated-tau using multiplexed Luminex assays biomarker values were used to generate decision-tree algorithms (classification and regression tree) in the R statistical software environment. The best decision tree model had an accuracy of 74.65% to differentiate the three groups. Cluster analysis supported the combination of CSF biomarkers to differentiate AD and MCI vs. controls, suggesting the best cutoff values for each clinical condition. Automated analyses of AD biomarkers provide valuable information to support the clinical diagnosis of MCI and AD in research settings.

Announcement of the diagnosis of Alzheimers disease or a related disorder in a geriatric short-stay unit.

The disclosure of the diagnosis of Alzheimers disease or a related disorder, or rather the time of the diagnostic disclosure, is a crucial step in the care of people with these neurocognitive diseases. While the disclosure procedures are well defined for practitioners who work in memory consultations, there is a grey area for hospital professionals who work in acute medical units.

Therapeutic nanotechnologies for Alzheimers disease A critical analysis of recent trends and findings.

Alzheimers Disease (AD) is an irreversible neurodegenerative disease for which no modifying therapies are presently available. Besides the identification of pathological targets, AD presents numerous clinical and pharmacological challenges such as efficient active delivery to the central nervous system, cell targeting, and long-term dosing. Nanoparticles have been explored to overcome some of these challenges as drug delivery vehicles or drugs themselves. However, early promises have failed to materialize as no nanotechnology-based product has been able to reach the market and very few have moved past preclinical stages. In this review, we perform a critical analysis of the past decades research on nanomedicine-based therapies for AD at the preclinical and clinical stages. The main obstacles to nanotechnology products and the most promising approaches were also identified, including renewed promise with gene editing, gene modulation, and vaccines.

Genetic and environmental influences on structural- and diffusion-based Alzheimers disease neuroimaging signatures across midlife and early old age.

Composite scores of MRI-derived metrics in brain regions associated with Alzheimers disease (AD), commonly termed AD signatures, have been developed to distinguish early AD-related atrophy from normal age-associated changes. Diffusion-based gray matter signatures may be more sensitive to early AD-related changes compared to thicknessvolume-based signatures, demonstrating their potential clinical utility. The timing of early (i.e., midlife) changes in AD signatures from different modalities, and whether diffusion- and thicknessvolume-based signatures each capture unique, AD-related phenotypic or genetic information, remains unknown. Our validated thicknessvolume signature, our novel mean diffusivity (MD) signature, and an MRI-derived measure of brain age were used in biometrical analyses to examine genetic and environmental influences on the measures, as well as phenotypic and genetic relationships between measures over 12 years. Participants were 736 men from three waves of the Vietnam Era Twin Study of Aging (VETSA baseline age56.1, SD2.6, range51.1-60.2). Subsequent waves were at approximately 5.7-year intervals. MD and thicknessvolume signatures were highly heritable (56-72%). Baseline MD signatures predicted thicknessvolume signatures over a decade later, but baseline thicknessvolume signatures showed a significantly weaker relationship with future MD signatures. AD signatures and brain age were correlated, but each measure captured unique phenotypic and genetic variance. Cortical MD and thicknessvolume AD signatures are heritable, and each signature captures unique variance that is also not explained by brain age. Moreover, results are in line with changes in MD emerging before changes in cortical thickness, underscoring the utility of MD as a very early predictor of AD risk.

Protective effect of vitamin C on DNA damage in surgery-induced cognitive dysfunction in APPPS1 mice.

Postoperative cognitive impairment is more likely to occur in elderly patients and in those with neurodegenerative diseases. The mechanisms underlying this impairment include neuroinflammation and oxidative stress. The increase in reactive oxygen species during oxidative stress causes cellular and molecular injury to neurons, including DNA damage, which aggravate brain dysfunction. Vitamin C has antioxidant effects and improves cognitive function in patients with Alzheimers disease. However, it is unclear whether it can ameliorate surgery-induced cognitive impairment by inhibiting oxidative stress. In this study, 6-month-old mice overexpressing mutant amyloid precursor protein and presenilin-1 (APPPS1) were subjected to laparotomy. The open field and fear conditioning tests were used to assess cognitive function. Mice that underwent surgery showed cognitive impairment without changes in spontaneous locomotor activity. Oxidative stress, DNA damage and inflammatory mediators were increased in the hippocampus after surgery. The expression levels of non-homologous end-joining DNA repair-associated proteins, including Ku heterodimer, DNA-dependent protein kinase catalytic subunit, X-ray repair cross complementing 4 (XRCC4) and XRCC4-like factor, were increased after surgery. Vitamin C pretreatment effectively attenuated cognitive dysfunction induced by surgery and reduced oxidative stress and DNA damage. Our findings suggest that DNA damage plays an important role in surgery-induced cognitive dysfunction, and that vitamin C pretreatment may have therapeutic potential as a preventative approach for the cognitive impairment.

Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimers disease.

Alzheimers disease (AD) is one of the foremost neurodegenerative diseases, characterized by beta-amyloid (Aβ) plaques and significant progressive memory loss. In AD, astrocytes are proposed to take up and clear Aβ plaques. However, how Aβ induces pathogenesis and memory impairment in AD remains elusive. We report that normal astrocytes show non-cyclic urea metabolism, whereas Aβ-treated astrocytes show switched-on urea cycle with upregulated enzymes and accumulated entering-metabolite aspartate, starting-substrate ammonia, end-product urea, and side-product putrescine. Gene silencing of astrocytic ornithine decarboxylase-1 (ODC1), facilitating ornithine-to-putrescine conversion, boosts urea cycle and eliminates aberrant putrescine and its toxic byproducts ammonia and H

A modeling study of the effect of an alternating magnetic field on magnetite nanoparticles in proximity of the neuronal microtubules A proposed mechanism for detachment of tau proteins.

It is known that the disintegration of microtubules in neurons occurs in response to the phosphorylation of the tau proteins that promotes the structural instability of the microtubules, as one of the factors underlying the onset of Alzheimers disease (AD). In this study, the mechanical variations undergone by the tau proteins and microtubules structures due to the action of intrinsic magnetite nanoparticles inside the brain tissue have been computationally modeled using the finite element (FEM) method. The von Mises stress induced by magnetite nanoparticles, subject to an applied alternating magnetic field, leads to local heating and mechanical forces, prompting a corresponding deformation in, and displacement of, the microtubule and the tau protein. The induction of these deformations would increase the probability of the microtubules depolymerization, and hence their eventual structural disintegration.

Predictive Accuracy of Digital Biomarker Technologies for Detection of Mild Cognitive Impairment and Pre-Frailty Amongst Older Adults A Systematic Review and Meta-Analysis.

Digital biomarker technologies coupled with predictive models are increasingly applied for early detection of age-related potentially reversible conditions including mild cognitive impairment (MCI) and pre-frailty (PF). We aimed to determine the predictive accuracy of digital biomarker technologies to detect MCI and PF with systematic review and meta-analysis. A computer-assisted search on major academic research databases including IEEE-Xplore was conducted. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines were adopted for reporting in this study. Summary receiver operating characteristic curve based on random-effect bivariate model was used to evaluate overall sensitivity and specificity for detection of the respective age-related conditions. A total of 43 studies were selected for final systematic review and meta-analysis. 26 studies reported on detection of MCI with sensitivity and specificity of 0.48-1.00 and 0.55-1.00, respectively. On the other hand, there were 17 studies that reported on the detection of PF with reported sensitivity of 0.53-1.00 and specificity of 0.61-1.00. Meta-analysis further revealed pooled sensitivities of 0.84 (95% CI 0.79-0.88) and 0.82 (95% CI 0.74-0.88) for in-home detection of MCI and PF, respectively, while pooled specificities were 0.85 (95% CI 0.80-0.89) and 0.82 (95% CI 0.75-0.88), respectively. Besides MCI, and PF, in this work during systematic review, we also found one study which reported a sensitivity of 0.93 and a specificity of 0.57 for detection of cognitive frailty (CF). The meta-analytic result, for the first time, quantifies the predictive efficacy of digital biomarker technologies for detection of MCI and PF. Additionally, we found the number of studies for detection of CF to be notably lower, indicating possible research gaps to explore predictive models on digital biomarker technology for detection of CF.

Verbal fluency discrepancies as a marker of the prehippocampal stages of Alzheimers disease.

Prior to evidence of episodic memory decline, a lengthy preclinical phase of Alzheimers disease (AD) exists characterized by the build-up of tau pathology within extrahippocampal structures. Semantic memory, also impaired in AD, has been linked to degradation within these earliest affected areas. This study aimed to assess the utility of performance discrepancies between letter and category verbal fluency tasks to detect neuronal loss in brain regions affected very early by AD. Whole-brain voxel-based morphometry was used to assess the neural correlates of semantic processing in three patient groups two groups of mild cognitive impairment (MCI) patients split into mildly ( Patients at all disease stages demonstrated a loss of the normal semantic advantage in fluency tests, showing significantly greater impairments in category relative to letter fluency. Discrepancy scores in mild MCI correlated strongly with the structural integrity of the anterior medial temporal lobes. Correlations in more severely affected groups were weaker and more widespread. Semantic memory appears a useful indicator of even the earliest stages of medial temporal damage in AD. With advancing disease severity, the discrepancy index loses its focal anatomical association, reinforcing its value as an early marker of incipient decline. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Toxicity Mechanism of Aβ42 Oligomer in the Binding between the GABA

Amyloid-β peptide (Aβ), characterized by its abnormal folding into neurotoxic aggregates, impairs synaptic plasticity and causes synaptic loss associated with Alzheimers disease (AD). The neurotoxicity of Aβ oligomers via the binding to various cell-surface receptors was frequently observed experimentally however, the toxic mechanism still remains unknown. In this paper, we study the intervention of Aβ oligomers to the receptor-peptide binding in the GABA

Associations Between Handgrip Strength and Dementia Risk, Cognition, and Neuroimaging Outcomes in the UK Biobank Cohort Study.

The associations between muscle strength and cognitive outcomes have sparked interest in interventions that increase muscle strength for prevention of dementia, but the associations between muscle strength and cognitive aging are unclear, particularly among middle-aged adults. To evaluate the association between handgrip strength (HGS) and dementia, reduced cognition, and poorer neuroimaging outcomes in a UK population of middle-aged adults. This cohort study evaluated UK Biobank participants aged 39 to 73 years enrolled from 2006 to 2010 with measured HGS and prospectively followed up for dementia diagnosis. Data were analyzed from October 2021 to April 2022. HGS assessed in both hands via dynamometer. Outcomes included cognitive test scores (fluid intelligence and prospective memory), brain magnetic resonance imaging measures (total brain volume, white matter hyperintensity, and hippocampal volume), and incident dementia (all-cause, vascular, and Alzheimer disease AD from primary care, hospital, or death records) over a median (IQR) of 11.7 (11.0-12.4) years of follow-up. Mixed-effects linear and logistic regressions and Cox proportional-hazard models were used to estimate associations, stratified by gender and adjusted for covariates. Estimates are presented per 5-kg decrement in HGS. To evaluate reverse causation, we assessed whether a polygenic risk score for AD is associated with HGS. A subsample of 190 406 adult participants in the UK Biobank (mean SD age, 56.5 8.1 years 102 735 women 54%) were evaluated. A 5-kg decrement in HGS was associated with lower fluid intelligence scores in men (β, -0.007 95% CI, -0.010 to -0.003) and women (β, -0.04 95% CI, -0.05 to -0.04. A 5-kg decrement in HGS was associated with worse odds of correctly responding to a prospective memory task for men (odds ratio, 0.91 95% CI, 0.90 to 0.92) and women (odds ratio, 0.88 95% CI, 0.87 to 0.90). A 5-kg decrement in HGS was associated with greater white matter hyperintensity volume in men (β, 92.22 95% CI, 31.09 to 153.35) and women (β, 83.56 95% CI, 13.54 to 153.58). A 5-kg decrement in HGS was associated with incident dementia for men (hazard ratio, 1.20 95% CI, 1.12 to 1.28) and women (hazard ratio, 1.12 95% CI, 1.00 to 1.26). The AD genetic risk score was not significantly associated with HGS. These findings suggest that HGS is associated with measures of neurocognitive brain health among men and women and they add to a growing body of research indicating that interventions designed to increase muscle strength, particularly among middle-aged adults, may hold promise for the maintenance of neurocognitive brain health.

Alzheimers disease pattern derived from relative cerebral flow as an alternative for the metabolic pattern using SSMPCA.

2-Deoxy-2- In general, the rCBF and FDG AD-DPs were characterized by a reduction in cortical frontal, temporal, and parietal lobes. FDG and rCBF methods presented similar score distribution. rCBF images may provide an alternative for FDG PET scans for the identification of AD patients through SSMPCA.

Cerebrospinal fluid levels of proenkephalin and prodynorphin are differentially altered in Huntingtons and Parkinsons disease.

Proenkephalin (PENK) and prodynorphin (PDYN) are peptides mainly produced by the striatal medium spiny projection neurons (MSNs) under dopaminergic signaling. Therefore, they may represent candidate biomarkers in Huntingtons disease (HD) and Parkinsons disease (PD), two neurodegenerative diseases characterized by striatal atrophy andor dysfunction. Using an in-house established liquid chromatography-tandem mass spectrometry (LC-MSMS) method in multiple reaction monitoring mode (MRM) we measured cerebrospinal fluid (CSF) levels of PENK- and PDYN- derived peptides in patients with HD (n 47), PD (n 61), Alzheimers disease (n 11), amyotrophic lateral sclerosis (n 14) and in 92 control subjects. Moreover, we investigated the possible associations between biomarkers and disease severity scales in HD and PD and the effect of dopaminergic therapy on biomarker levels in PD. In HD, CSF PENK- and PDYN-derived peptide levels were significantly decreased compared to all other groups and were associated with disease severity scores. In PD, both biomarkers were within the normal range, but higher PDYN levels were found in dopamine-treated compared to untreated patients. In PD, both CSF PENK and PDYN did not correlate with clinical severity scales. CSF PENK- and PDYN-derived peptides appeared to be promising pathogenetic and disease severity markers in HD, reflecting the ongoing striatal neurodegeneration along with the loss of MSNs. In PD patients, CSF PDYN showed a limitative role as a possible pharmacodynamic marker during dopaminergic therapy, but further investigations are needed.

Mass Spectrometry-Based Analysis of Lipid Involvement in Alzheimers Disease Pathology-A Review.

Irregularities in lipid metabolism have been linked to numerous neurodegenerative diseases. The roles of abnormal brain, plasma, and cerebrospinal fluid (CSF) lipid levels in Alzheimers disease (AD) onset and progression specifically have been described to a great extent in the literature. Apparent hallmarks of AD include, but are not limited to, genetic predisposition involving the APOE Ɛ4 allele, oxidative stress, and inflammation. A common culprit tied to many of these hallmarks is disruption in brain lipid homeostasis. Therefore, it is important to understand the roles of lipids, under normal and abnormal conditions, in each process. Lipid influences in processes such as inflammation and blood-brain barrier (BBB) disturbance have been primarily studied via biochemical-based methods. There is a need, however, for studies focused on uncovering the relationship between lipid irregularities and AD by molecular-based quantitative analysis in transgenic animal models and human samples alike. In this review, mass spectrometry as it has been used as an analytical tool to address the convoluted relationships mentioned above is discussed. Additionally, molecular-based mass spectrometry strategies that should be used going forward to further relate structure and function relationships of lipid irregularities and hallmark AD pathology are outlined.

Folate Related Pathway Gene Analysis Reveals a Novel Metabolic Variant Associated with Alzheimers Disease with a Change in Metabolic Profile.

Metabolic disorders may be important potential causative pathways to Alzheimers disease (AD). Cerebrospinal fluid (CSF) decreasing output, raised intracranial pressure, and ventricular enlargement have all been linked to AD. Cerebral folate metabolism may be a key player since this is significantly affected by such changes in CSF, and genetic susceptibilities may exist in this pathway. In the current study, we aimed to identify whether any single nucleotide polymorphism (SNPs) affecting folate and the associated metabolic pathways were significantly associated with AD. We took a functional nutrigenomics approach to look for SNPs in genes for the linked folate, methylation, and biogenic amine neurotransmitter pathways. Changes in metabolism were found with the SNPs identified. An abnormal SNP in methylene tetrahydrofolate dehydrogenase 1 (

Biological Potential, Gastrointestinal Digestion, Absorption, and Bioavailability of Algae-Derived Compounds with Neuroprotective Activity A Comprehensive Review.

Currently, there is no known cure for neurodegenerative disease. However, the available therapies aim to manage some of the symptoms of the disease. Human neurodegenerative diseases are a heterogeneous group of illnesses characterized by progressive loss of neuronal cells and nervous system dysfunction related to several mechanisms such as protein aggregation, neuroinflammation, oxidative stress, and neurotransmission dysfunction. Neuroprotective compounds are essential in the prevention and management of neurodegenerative diseases. This review will focus on the neurodegeneration mechanisms and the compounds (proteins, polyunsaturated fatty acids (PUFAs), polysaccharides, carotenoids, phycobiliproteins, phenolic compounds, among others) present in seaweeds that have shown in vivo and in vitro neuroprotective activity. Additionally, it will cover the recent findings on the neuroprotective effects of bioactive compounds from macroalgae, with a focus on their biological potential and possible mechanism of action, including microbiota modulation. Furthermore, gastrointestinal digestion, absorption, and bioavailability will be discussed. Moreover, the clinical trials using seaweed-based drugs or extracts to treat neurodegenerative disorders will be presented, showing the real potential and limitations that a specific metabolite or extract may have as a new therapeutic agent considering the recent approval of a seaweed-based drug to treat Alzheimers disease.

Cognitive Decline in Older People with Multiple Sclerosis-A Narrative Review of the Literature.

Several important questions regarding cognitive aging and dementia in older people with multiple sclerosis (PwMS) are the focus of this narrative review Do older PwMS have worse cognitive decline compared to older people without MS Can older PwMS develop dementia or other neurodegenerative diseases such as Alzheimers disease (AD) that may be accelerated due to MS Are there any potential biomarkers that can help to determine the etiology of cognitive decline in older PwMS What are the neural and cellular bases of cognitive aging and neurodegeneration in MS Current evidence suggests that cognitive impairment in MS is distinguishable from that due to other neurodegenerative diseases, although older PwMS may present with accelerated cognitive decline. While dementia is prevalent in PwMS, there is currently no consensus on defining it. Cerebrospinal fluid and imaging biomarkers have the potential to identify disease processes linked to MS and other comorbidities-such as AD and vascular disease-in older PwMS, although more research is required. In conclusion, one should be aware that multiple underlying pathologies can coexist in older PwMS and cause cognitive decline. Future basic and clinical research will need to consider these complex factors to better understand the underlying pathophysiology, and to improve diagnostic accuracy.

Alzheimers disease cerebrospinal fluid biomarkers differentiate patients with Creutzfeldt-Jakob disease and autoimmune encephalitis.

Autoimmune encephalitis (AE) is a potentially treatable cause of rapidly progressive dementia that may mimic Creutzfeldt-Jakob disease (CJD). Alzheimer disease (AD) cerebrospinal fluid (CSF) biomarkers may discriminate CJD from AD, but utility in discriminating CJD and AE is unclear. This study compared AD CSF biomarkers in CJD and AE. Patients with probable or definite CJD and probable or definite AE who underwent Roche Elecsys AD CSF biomarker testing at Mayo Clinic from March 2020 through April 2021 were included. Total-tau, phosphorylated Of 11 CJD cases, four were autopsy proven the rest had positive real-time quaking-induced conversion testing. Disease-associated autoantibodies were detected in 815 cases of AE leucine-rich glioma-inactivated 1 and neuronal intermediate filaments (two cases each), and N-methyl-d-aspartate receptor, contactin-associated protein-like 2, dipeptidyl-peptidase-like protein 6 and immunoglobulin-like cell adhesion molecule IgLON family member 5. Total-tau provided excellent discrimination between CJD and AE in a univariate model (odds ratio 1.46 per 100 pgml, 95% confidence interval 1.17-2.11, p < 0.05, c 0.93). Total-tau was elevated in 91% of CJD cases (median > 1300, range 236->1300 pgml), of which 55% were above the limit of assay measurement (>1300 pgml). Total-tau was elevated in 20% of AE cases (median 158, range 80->1300 pgml). Total-tau was greater in CJD than AE. Given that amyloid-β

LC-MSMS assay of fluoropezil and its two major metabolites in human plasma an application to pharmacokinetic studies.

Digital Analysis of Smart Registration Methods for Magnetic Resonance Images in Public Healthcare.

Brain development and atrophy accompany peoples life. Brain development diseases, such as autism and Alzheimers disease, affect a large part of the population. Analyzing brain development is very important in public healthcare, and image registration is essential in medical brain image analysis. Many previous studies investigate registration accuracy by the ground truth dataset, marker-based similarity calculation, and expert check to find the best registration algorithms. But the evaluation of image registration technology only at the accuracy level is not comprehensive. Here, we compare the performance of three publicly available registration techniques in brain magnetic resonance imaging (MRI) analysis based on some key features widely used in previous MRI studies for classification and detection tasks. According to the analysis results, SPM12 has a stable speed and success rate, and it always works as a guiding tool for newcomers to medical image analysis. It can preserve maximum contrast information, which will facilitate studies such as tumor diagnosis. FSL is a mature and widely applicable toolkit for users, with a relatively stable success rate and good performance. It has complete functions and its function-based integrated toolbox can meet the requirements of different researchers. AFNI is a flexible and complex tool that is more suitable for professional researchers. It retains most details in medical image analysis, which makes it useful in fine-grained analysis such as volume estimation. Our study provides a new idea for comparing registration tools, where tool selection strategy mainly depends on the research task in which the selected tool can leverage its unique advantages.

Non-invasive brain stimulation and neuroenhancement.

Attempts to enhance human memory and learning ability have a long tradition in science. This topic has recently gained substantial attention because of the increasing percentage of older individuals worldwide and the predicted rise of age-associated cognitive decline in brain functions. Transcranial brain stimulation methods, such as transcranial magnetic (TMS) and transcranial electric (tES) stimulation, have been extensively used in an effort to improve cognitive functions in humans. Here we summarize the available data on low-intensity tES for this purpose, in comparison to repetitive TMS and some pharmacological agents, such as caffeine and nicotine. There is no single area in the brain stimulation field in which only positive outcomes have been reported. For self-directed tES devices, how to restrict variability with regard to efficacy is an essential aspect of device design and function. As with any technique, reproducible outcomes depend on the equipment and how well this is matched to the experience and skill of the operator. For self-administered non-invasive brain stimulation, this requires device designs that rigorously incorporate human operator factors. The wide parameter space of non-invasive brain stimulation, including dose (e.g., duration, intensity (current density), number of repetitions), inclusionexclusion (e.g., subjects age), and homeostatic effects, administration of tasks before and during stimulation, and, most importantly, placebo or nocebo effects, have to be taken into account. The outcomes of stimulation are expected to depend on these parameters and should be strictly controlled. The consensus among experts is that low-intensity tES is safe as long as tested and accepted protocols (including, for example, dose, inclusionexclusion) are followed and devices are used which follow established engineering risk-management procedures. Devices and protocols that allow stimulation outside these parameters cannot claim to be safe where they are applying stimulation beyond that examined in published studies that also investigated potential side effects. Brain stimulation devices marketed for consumer use are distinct from medical devices because they do not make medical claims and are therefore not necessarily subject to the same level of regulation as medical devices (i.e., by government agencies tasked with regulating medical devices). Manufacturers must follow ethical and best practices in marketing tES stimulators, including not misleading users by referencing effects from human trials using devices and protocols not similar to theirs.

Spatial Distribution and Hierarchical Clustering of β-Amyloid and Glucose Metabolism in Alzheimers Disease.

Increased amyloid burden and decreased glucose metabolism are important characteristics of Alzheimers disease (AD), but their spatial distribution and hierarchical clustering organization are still poorly understood. In this study, we explored the distribution and clustering organization of amyloid and glucose metabolism based on

Technical Performance Evaluation of Olink Proximity Extension Assay for Blood-Based Biomarker Discovery in Longitudinal Studies of Alzheimers Disease.

The core Alzheimers disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-β (Aß), total tau (t-tau), and phosphorylated tau (p-tau181), are strong indicators of the presence of AD pathology, but do not correlate well with disease progression, and can be difficult to implement in longitudinal studies where repeat biofluid sampling is required. As a result, blood-based biomarkers are increasingly being sought as alternatives. In this study, we aimed to evaluate a promising blood biomarker discovery technology, Olink Proximity Extension Assays for technical reproducibility characteristics in order to highlight the advantages and disadvantages of using this technology in biomarker discovery in AD. We evaluated the performance of five Olink Proteomic multiplex proximity extension assays (PEA) in plasma samples. Three technical control samples included on each plate allowed calculation of technical variability. Biotemporal stability was measured in three sequential annual samples from 54 individuals with and without AD. Coefficients of variation (CVs), analysis of variance (ANOVA), and variance component analyses were used to quantify technical and individual variation over time. We show that overall, Olink assays are technically robust, with the largest experimental variation stemming from biological differences between individuals for most analytes. As a powerful illustration of one of the potential pitfalls of using a multi-plexed technology for discovery, we performed power calculations using the baseline samples to demonstrate the size of study required to overcome the need for multiple test correction with this technology. We show that the power of moderate effect size proteins was strongly reduced, and as a result investigators should strongly consider pooling resources to perform larger studies using this multiplexed technique where possible.

Disturbance of Ecological Self and Impairment of Affordance Perception.

Affordance, a radical concept James Gibson introduced in the 1970s, remains controversial today. Defined as environmental properties taken with reference to an animals anatomy and action capabilities, affordances are opportunities for action the environment offers. By perceiving affordances, organisms hold meaningful relationships with their surroundings. Affordance is not just a theoretical concept but, as the embodiment of meanings and values, has serious psychological implications. We contend that the lack of these meanings and values underlies the irrational behavior seen in patients with self disorders such as schizophrenia. We reason that it is by perceiving affordances that individuals keep in touch with their surroundings and stay mentally healthy. Using contrapositive reasoning, the reverse could also be true. That is, when individuals experience difficulty maintaining meaningful relations with their surroundings and suffer from mental health problems, we might anticipate that their affordance detection systems are impaired. In two studies conducted in our laboratory, patients with schizophrenia and Alzheimers disease were shown to have impaired capacity to perceive affordances, a result qualifying as contra-positive evidence corroborating the affordance concept. In addition, our results provide support for accepting contra-positive evidence as a complementary tool to positive evidence for empirically validating concepts such as affordance and meaning.

Practical Considerations in the Administration of Aducanumab for the Neurologist.

Aducanumab (Aduhelm), developed by the biotechnology firm Biogen in Cambridge, MA, was approved using the less common accelerated approval pathway by the Federal Drug Administration (FDA) reserved for treatments that fill a significant unmet need.

Prevalence, Influencing Factors, and Clinical Characteristics of Cognitive Impairment in Elderly Patients With Schizophrenia.

The purpose of this study was to investigate the prevalence, influencing factors, and clinical characteristics of cognitive impairment in elderly patients with chronic schizophrenia. A total of 264 elderly patients with chronic schizophrenia and 156 normal controls were enrolled in the current study. The Mini-mental State Examination (MMSE) was used to assess their overall cognitive function, the Positive And Negative Syndrome Scale (PANSS) was used to assess their psychotic symptoms, the Geriatric Depression Scale (GDS) was used to assess their depressive symptoms, while Activity of Daily Living Scale (ADL) was used to assess their daily living ability. The prevalence of cognitive impairment was 77.7% (205264) in elderly patients with chronic schizophrenia, which was much higher than that 16.7% (26156) in normal controls. By using stepwise binary regression analysis, we found that hobbies ( Cognitive impairment is a very prominent problem in elderly patients with chronic schizophrenia. Elderly schizophrenia patients with cognitive impairment tended to have more depressive mood, more psychotic symptoms and worse activities of daily living. Hobbies will help prevent cognitive impairment in elderly patients with schizophrenia and may improve their cognitive function by influencing psychiatric symptoms. Therefore, we should encourage elderly patients with chronic schizophrenia to develop their own hobbies. However, the above conclusion still need to be further verified, as we cannot exclude the effects of age and education.

Sleep and Alzheimer The Link.

Alzheimers disease is the most common type of dementia which has both cognitive and non-cognitive disabilities. Recent research has proved that sleep deprivation and insomnia have been related to the pathophysiology of Alzheimers disease and would influence the symptoms and progression of the disease. We look at the current research that supports the idea that the lack of sleep relates to cognitive decline and dementia, with an emphasis on Alzheimers disease. We integrated the various possible mechanisms of sleep deprivation leading to Alzheimers disease and cognitive decline. The role of neuroinflammation, generation of reactive oxidative species and sleep disturbances play a central role in tau generation and Aβ deposition. An approach to manage sleep changes can widely prevent the cognitive decline of Alzheimers disease.

Functional Connectivity and Complexity in the Phenomenological Model of Mild Cognitive-Impaired Alzheimers Disease.

Functional connectivity and complexity analysis has been discretely studied to understand intricate brain dynamics. The current study investigates the interplay between functional connectivity and complexity using the Kuramoto mean-field model. Functional connectivity matrices are estimated using the weighted phase lag index and complexity measures through popularly used complexity estimators such as Lempel-Ziv complexity (LZC), Higuchis fractal dimension (HFD), and fluctuation-based dispersion entropy (FDispEn). Complexity measures are estimated on real and simulated electroencephalogram (EEG) signals of patients with mild cognitive-impaired Alzheimers disease (MCI-AD) and controls. Complexity measures are further applied to simulated signals generated from lesion-induced connectivity matrix and studied its impact. It is a novel attempt to study the relation between functional connectivity and complexity using a neurocomputational model. Real EEG signals from patients with MCI-AD exhibited reduced functional connectivity and complexity in anterior and central regions. A simulation study has also displayed significantly reduced regional complexity in the patient group with respect to control. A similar reduction in complexity was further evident in simulation studies with lesion-induced control groups compared with non-lesion-induced control groups. Taken together, simulation studies demonstrate a positive influence of reduced connectivity in the model imparting a reduced complexity in the EEG signal. The study revealed the presence of a direct relation between functional connectivity and complexity with reduced connectivity, yielding a decreased EEG complexity.

Network-level permutation entropy of resting-state MEG recordings A novel biomarker for early-stage Alzheimers disease

Increasing evidence suggests that measures of signal variability and complexity could present promising biomarkers for Alzheimers disease (AD). Earlier studies have however been limited to the characterization of local activity. Here, we investigate whether a network version of permutation entropy could serve as a novel biomarker for early-stage AD. Resting-state source-space magnetoencephalography was recorded in 18 subjects with subjective cognitive decline (SCD) and 18 subjects with mild cognitive impairment (MCI). Local activity was characterized by permutation entropy (PE). Network-level interactions were studied using the inverted joint permutation entropy (JPE

Abnormal whisker movements in the 3xTg-AD mouse model of Alzheimers disease.

Alzheimers disease is the most frequent form of dementia in elderly people. The triple transgenic (3xTg-AD) mouse model of Alzheimers Disease is important in biomedical research as these mice develop both neuropathological and behavioural phenotypes. However, their behavioural phenotype is variable, with findings depending on the specific task, as well as the age and sex of the mice. Whisker movements show motor, sensory and cognitive deficits in mouse models of neurodegenerative disease. Therefore, we examined whisker movements in 3, 12.5 and 17-month-old female 3xTg-AD mice and their B6129SF2 wildtype controls. Mice were filmed using a high-speed video camera (500 fps) in an open arena during a novel object exploration task. Genotype and age differences were found in mice exploring the arena prior to object contact. Prior to whisker contact, the 3-month-old 3xTg-AD mice had smaller whisker angles compared with the wildtype controls, suggesting an early motor phenotype in these mice. Pre-contact mean angular position at 3 months and whisking amplitude at 17 months of age differed between the 3xTg-AD and wildtype mice. During object contact 3xTg-AD mice did not reduce whisker spread as frequently as the wildtype mice at 12.5 and 17 months, which may suggest sensory or attentional deficits. We show that whisker movements are a powerful behavioural measurement tool for capturing behavioural deficits in mouse models that show complex phenotypes, such as the 3xTg-AD mouse model.

Foresee novel targets for Alzheimers disease by investigating repurposed drugs.

Alzheimers Disease (AD) is the most rampant neurodegenerative disorder which has caused havoc worldwide. More than a century has passed since the first case of AD was reported, but still no stable treatment is known to mankind. The available medications only provide temporary relief and are not a cure for the disease. The hunt for advanced techniques in drug development has paved the way for drug repurposing, i.e., repositioning or reutilizing drugs as an innovative approach. Several drugs which were repurposed for AD were collected by following PRISMA 2020 systemic review. Databases like PubMed, ScienceDirect, JSTOR, and SciELO were used for data extraction. Further, Drugbank database was used to download all the identified drugs. Later, the Swiss Target Prediction tool was used to identify protein receptors for these drugs and the biological pathway followed by them. Drugs like Zileuton, Salbutamol, Baricitinib, Carmustine, Paclitaxel, and Nilotinib were observed to be involved in regulation of neurotransmitters. Similarly, Metformin, Liraglutide, UDCA, and Bexarotene are involved in protein kinase cascades which also is one of the prime processes in metabolic disorders like AD. Furthermore, drugs like Rosiglitazone, Pioglitazone, and Lonafarnib are involved in interleukin-3 biosynthetic processes, which is again one of the most important processes studied in AD treatment. The study concluded that the reviewed drugs that follow similar biological and molecular processes can be repurposed for AD if chosen judiciously with current medications and thus drug repurposing is a promising approach that can be utilized to find a cure for AD within a brief time and fewer resources compared to de novo drug synthesis. Although certain loopholes still need to be worked upon, the technique has great prospects. Furthermore, in silico methods can be utilized to justify the findings and identify the best drug candidate.