Search results for: alzheimer’s

Authors: Ghazal Mortazavi, S. M. J. Mortazavi

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Electricians, power line engineers and power station workers, welders, aluminum reduction workers, MRI operators and railway workers are occupationally exposed to different levels of electromagnetic fields. Mercury is among the most toxic metals. Dental amalgam fillings cause significant exposure to elemental mercury vapour in the general population. Today, substantial evidence indicates that mercury even at low doses may lead to toxicity. Increased release of mercury from dental amalgam fillings after exposure to MRI or microwave radiation emitted by mobile phones has been previously shown by our team. Moreover, our recent studies on the effects of stronger magnetic fields entirely confirmed our previous findings. From the other point of view, we have also shown that papers which reported no increased release of mercury after MRI, may have some methodological flaws. Over the past several years, our lab has focused on the health effects of exposure of laboratory animals and humans to different sources of electromagnetic fields such as mobile phones and their base stations, mobile phone jammers, laptop computers, radars, dentistry cavitrons, and MRI. As a strong association between exposure to electromagnetic fields and mercury level has been found in our studies, our findings lead us to this conclusion that occupational exposure to electromagnetic fields in workers with dental amalgam fillings can lead to elevated levels of mercury. Studies which reported that exposure to mercury can be a risk factor of Alzheimer’s disease (AD) due to the accumulation of amyloid beta protein (Aβ) in the brain and those reported that long-term occupational exposure to high levels of electromagnetic fields can increase the risk of Alzheimer's disease and dementia in male workers support our concept and confirm the significant role of the occupational exposure to electromagnetic fields in increasing the mercury level in workers with amalgam fillings.

Keywords: occupational exposure, electromagnetic fields, workers, mercury release, dental amalgam, restorative dentistry

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Authors: Linyi Fan, C.J. Schumaker

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Background: Biomedical efforts to treat Alzheimer’s disease (AD) have typically produced mixed to poor results, while more lifestyle-focused treatments such as exercise may fare better than existing biomedical treatments. A few promising studies have indicated that activities of daily life (ADL) may be a useful way of predicting AD. However, the existing cross-sectional studies fail to show how functional-related issues such as ADL in early years predict AD and how social factors influence health either in addition to or in interaction with individual risk factors. This study would helpbetterscreening and early treatments for the elderly population and healthcare practice. The findings have significance academically and practically in terms of creating positive social change. Methodology: The purpose of this quantitative historical, correlational study was to examine the relationship between early years’ ADL and the development of AD in later years. The studyincluded 4,526participantsderived fromRAND HRS dataset. The Health and Retirement Study (HRS) is a longitudinal household survey data set that is available forresearchof retirement and health among the elderly in the United States. The sample was selected by the completion of survey questionnaire about AD and dementia. The variablethat indicates whether the participant has been diagnosed with AD was the dependent variable. The ADL indices and changes in ADL were the independent variables. A four-step multilevel regression model approach was utilized to address the research questions. Results: Amongst 4,526 patients who completed the AD and dementia questionnaire, 144 (3.1%) were diagnosed with AD. Of the 4,526 participants, 3,465 (76.6%) have high school and upper education degrees,4,074 (90.0%) were above poverty threshold. The model evaluatedthe effect of ADL and change in ADL on onset of AD in late years while allowing the intercept of the model to vary by level of education. The results suggested that the only significant predictor of the onset of AD was changes in early years’ ADL (b = 20.253, z = 2.761, p < .05). However, the result of the sensitivity analysis (b = 7.562, z = 1.900, p =.058), which included more control variables and increased the observation period of ADL, are not supported this finding. The model also estimated whether the variances of random effect vary by Level-2 variables. The results suggested that the variances associated with random slopes were approximately zero, suggesting that the relationship between early years’ ADL were not influenced bysociodemographic factors. Conclusion: The finding indicated that an increase in changes in ADL leads to an increase in the probability of onset AD in the future. However, this finding is not support in a broad observation period model. The study also failed to reject the hypothesis that the sociodemographic factors explained significant amounts of variance in random effect. Recommendations were then made for future research and practice based on these limitations and the significance of the findings.

Keywords: alzheimer’s disease, epidemiology, moderation, multilevel modeling

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Authors: Felice Elefant, Akanksha Bhatnaghar, Keegan Krick, Elizabeth Heller

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Context: The severity of Alzheimer’s Disease (AD) progression involves an interplay of genetics, age, and environmental factors orchestrated by histone acetyltransferase (HAT) mediated neuroepigenetic mechanisms. While disruption of Tip60 HAT action in neural gene control is implicated in AD, alternative mechanisms underlying Tip60 function remain unexplored. Altered RNA splicing has recently been highlighted as a widespread hallmark in the AD transcriptome that is implicated in the disease. Research Aim: The aim of this study was to identify a novel RNA binding/splicing function for Tip60 in human hippocampus and impaired in brains from AD fly models and AD patients. Methodology/Analysis: The authors used RNA immunoprecipitation using RNA isolated from 200 pooled wild type Drosophila brains for each of the 3 biological replicates. To identify Tip60’s RNA targets, they performed genome sequencing (DNB-SequencingTM technology, BGI genomics) on 3 replicates for Input RNA and RNA IPs by Tip60. Findings: The authors' transcriptomic analysis of RNA bound to Tip60 by Tip60-RNA immunoprecipitation (RIP) revealed Tip60 RNA targets enriched for critical neuronal processes implicated in AD. Remarkably, 79% of Tip60’s RNA targets overlap with its chromatin gene targets, supporting a model by which Tip60 orchestrates bi-level transcriptional regulation at both the chromatin and RNA level, a function unprecedented for any HAT to date. Since RNA splicing occurs co-transcriptionally and splicing defects are implicated in AD, the authors investigated whether Tip60-RNA targeting modulates splicing decisions and if this function is altered in AD. Replicate multivariate analysis of transcript splicing (rMATS) analysis of RNA-Seq data sets from wild-type and AD fly brains revealed a multitude of mammalian-like AS defects. Strikingly, over half of these altered RNAs were bonafide Tip60-RNA targets enriched for in the AD-gene curated database, with some AS alterations prevented against by increasing Tip60 in fly brain. Importantly, human orthologs of several Tip60-modulated spliced genes in Drosophila are well characterized aberrantly spliced genes in human AD brains, implicating disruption of Tip60’s splicing function in AD pathogenesis. Theoretical Importance: The authors' findings support a novel RNA interaction and splicing regulatory function for Tip60 that may underlie AS impairments that hallmark AD etiology. Data Collection: The authors collected data from RNA immunoprecipitation experiments using RNA isolated from 200 pooled wild type Drosophila brains for each of the 3 biological replicates. They also performed genome sequencing (DNBSequencingTM technology, BGI genomics) on 3 replicates for Input RNA and RNA IPs by Tip60. Questions: The question addressed by this study was whether Tip60 has a novel RNA binding/splicing function in human hippocampus and whether this function is impaired in brains from AD fly models and AD patients. Conclusions: The authors' findings support a novel RNA interaction and splicing regulatory function for Tip60 that may underlie AS impairments that hallmark AD etiology.

Keywords: Alzheimer's disease, cognition, aging, neuroepigenetics

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Authors: Dona Pamoda W. Jayatunga, Veer Bala Gupta, Eugene Hone, Ralph N. Martins

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Being a neurodegenerative disorder, Alzheimer’s disease (AD) affects a majority of the elderly demented worldwide. The key risk factors for AD are age, metabolic syndrome, allele status of APOE gene, head injuries and lifestyle. The progressive nature of AD is characterized by symptoms of multiple cognitive deficits exacerbated over time, leading to death within a decade from clinical diagnosis. However, it is revealed that AD originates via a prodromal phase that spans from one to few decades before symptoms first manifest. The key pathological hallmarks of AD brains are deposition of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFT). However, the yet unknown etiology of the disease fails to distinguish mitochondrial dysfunction between a cause or an outcome. The absence of early diagnosis tools and definite therapies for AD have permitted recruits of nutraceutical-based approaches aimed at reducing the risk of AD by modulating lifestyle or be used as preventive tools during AD prodromal state before widespread neurodegeneration begins. The objective of the present study was to investigate beneficial effects of luteolin, a plant-based flavone compound, against AD. The neuroprotective effects of luteolin on amyloid beta (Aβ) (1-42)-induced neurotoxicity was measured using cultured human neuroblastoma BE(2)-M17 cells. After exposure to 20μM Aβ (1-42) for 48 h, the neuroblastoma cells exhibited marked apoptotic death. Co-treatment of 20μM Aβ (1-42) with luteolin (0.5-5μM) significantly protected the cells against Aβ (1-42)-induced toxicity, as assessed by the MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2(4sulfophenyl)-2H-tetrazolium, inner salt; MTS] reduction assay and the lactate dehydrogenase (LDH) cell death assay. The results suggest that luteolin prevents Aβ (1-42)-induced apoptotic neuronal death. However, further studies are underway to determine its protective mechanisms in AD including the activity against tau hyperphosphorylation and mitochondrial dysfunction.

Keywords: Aβ (1-42)-induced toxicity, Alzheimer’s disease, luteolin, neuroblastoma cells

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Authors: Frederick Huie, Lauren Fusfeld, William Burchenal, Scott Howell, Alyssa McVey, Thomas F. Goss

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Alzheimer’s Disease (AD) is a degenerative brain disease characterized by memory loss and cognitive decline that presents a substantial economic burden for patients and health insurers in the US. This study evaluates the payer budget impact of the DISCERN™ test in the diagnosis and management of patients with symptoms of dementia evaluated for AD. DISCERN™ comprises three assays that assess critical factors related to AD that regulate memory, formation of synaptic connections among neurons, and levels of amyloid plaques and neurofibrillary tangles in the brain and can provide a quicker, more accurate diagnosis than tests in the current diagnostic pathway (CDP). An Excel-based model with a three-year horizon was developed to assess the budget impact of DISCERN™ compared with CDP in a Medicare Advantage plan with 1M beneficiaries. Model parameters were identified through a literature review and were verified through consultation with clinicians experienced in diagnosis and management of AD. The model assesses direct medical costs/savings for patients based on the following categories: •Diagnosis: costs of diagnosis using DISCERN™ and CDP. •False Negative (FN) diagnosis: incremental cost of care avoidable with a correct AD diagnosis and appropriately directed medication. •True Positive (TP) diagnosis: AD medication costs; cost from a later TP diagnosis with the CDP versus DISCERN™ in the year of diagnosis, and savings from the delay in AD progression due to appropriate AD medication in patients who are correctly diagnosed after a FN diagnosis.•False Positive (FP) diagnosis: cost of AD medication for patients who do not have AD. A one-way sensitivity analysis was conducted to assess the effect of varying key clinical and cost parameters ±10%. An additional scenario analysis was developed to evaluate the impact of individual inputs. In the base scenario, DISCERN™ is estimated to decrease costs by $4.75M over three years, equating to approximately $63.11 saved per test per year for a cohort followed over three years. While the diagnosis cost is higher with DISCERN™ than with CDP modalities, this cost is offset by the higher overall costs associated with CDP due to the longer time needed to receive a TP diagnosis and the larger number of patients who receive a FN diagnosis and progress more rapidly than if they had received appropriate AD medication. The sensitivity analysis shows that the three parameters with the greatest impact on savings are: reduced sensitivity of DISCERN™, improved sensitivity of the CDP, and a reduction in the percentage of disease progression that is avoided with appropriate AD medication. A scenario analysis in which DISCERN™ reduces the utilization for patients of computed tomography from 21% in the base case to 16%, magnetic resonance imaging from 37% to 27% and cerebrospinal fluid biomarker testing, positive emission tomography, electroencephalograms, and polysomnography testing from 4%, 5%, 10%, and 8%, respectively, in the base case to 0%, results in an overall three-year net savings of $14.5M. DISCERN™ improves the rate of accurate, definitive diagnosis of AD earlier in the disease and may generate savings for Medicare Advantage plans.

Keywords: Alzheimer’s disease, budget, dementia, diagnosis.

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Authors: Akanksha Bhatnagar, Sandhya Kortegare, Felice Elefant

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Context: Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by progressive cognitive decline and memory loss. The cause of AD is not fully understood, but it is thought to be caused by a combination of genetic, environmental, and lifestyle factors. One of the hallmarks of AD is the loss of neurons in the hippocampus, a brain region that is important for memory and learning. This loss of neurons is thought to be caused by a decrease in histone acetylation, which is a process that regulates gene expression. Research Aim: The research aim of the study was to develop mall molecule compounds that can enhance the activity of Tip60, a histone acetyltransferase that is important for memory and learning. Methodology/Analysis: The researchers used in silico structural modeling and a pharmacophore-based virtual screening approach to design and synthesize small molecule compounds strongly predicted to target and enhance Tip60’s HAT activity. The compounds were then tested in vitro and in vivo to assess their ability to enhance Tip60 activity and rescue cognitive deficits in AD models. Findings: The researchers found that several of the compounds were able to enhance Tip60 activity and rescue cognitive deficits in AD models. The compounds were also developed to cross the blood-brain barrier, which is an important factor for the development of potential AD therapeutics. Theoretical Importance: The findings of this study suggest that Tip60 HAT activators have the potential to be developed as therapeutic agents for AD. The compounds are specific to Tip60, which suggests that they may have fewer side effects than other HDAC inhibitors. Additionally, the compounds are able to cross the blood-brain barrier, which is a major hurdle for the development of AD therapeutics. Data Collection: The study collected data from a variety of sources, including in vitro assays and animal models. The in vitro assays assessed the ability of compounds to enhance Tip60 activity using histone acetyltransferase (HAT) enzyme assays and chromatin immunoprecipitation assays. Animal models were used to assess the ability of the compounds to rescue cognitive deficits in AD models using a variety of behavioral tests, including locomotor ability, sensory learning, and recognition tasks. The human clinical trials will be used to assess the safety and efficacy of the compounds in humans. Questions: The question addressed by this study was whether Tip60 HAT activators could be developed as therapeutic agents for AD. Conclusions: The findings of this study suggest that Tip60 HAT activators have the potential to be developed as therapeutic agents for AD. The compounds are specific to Tip60, which suggests that they may have fewer side effects than other HDAC inhibitors. Additionally, the compounds are able to cross the blood-brain barrier, which is a major hurdle for the development of AD therapeutics. Further research is needed to confirm the safety and efficacy of these compounds in humans.

Keywords: Alzheimer's disease, cognition, neuroepigenetics, drug discovery

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Authors: Alexandra K. Diem, Giles Richardson, Roxana O. Carare, Neil W. Bressloff

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Alzheimer's disease (AD) is the most common form of dementia and although it has been researched for over 100 years, there is still no cure or preventive medication. Its onset and progression is closely related to the accumulation of the neuronal metabolite Aβ. This raises the question of how metabolites and waste products are eliminated from the brain as the brain does not have a traditional lymphatic system. In recent years the rapid uptake of Aβ into cerebral artery walls and its clearance along those arteries towards the lymph nodes in the neck has been suggested and confirmed in mice studies, which has led to the hypothesis that interstitial fluid (ISF), in the basement membranes in the walls of cerebral arteries, provides the pathways for the lymphatic drainage of Aβ. This mechanism, however, requires a net reverse flow of ISF inside the blood vessel wall compared to the blood flow and the driving forces for such a mechanism remain unknown. While possible driving mechanisms have been studied using mathematical models in the past, a mechanism for net reverse flow has not been discovered yet. Here, we aim to address the question of the driving force of this reverse lymphatic drainage of Aβ (also called perivascular drainage) by using multi-scale numerical and analytical modelling. The numerical simulation software COMSOL Multiphysics 4.4 is used to develop a fluid-structure interaction model of a cerebral artery, which models blood flow and displacements in the artery wall due to blood pressure changes. An analytical model of a layer of basement membrane inside the wall governs the flow of ISF and, therefore, solute drainage based on the pressure changes and wall displacements obtained from the cerebral artery model. The findings suggest that an active role in facilitating a reverse flow is played by the components of the basement membrane and that stiffening of the artery wall during age is a major risk factor for the impairment of brain lymphatics. Additionally, our model supports the hypothesis of a close association between cerebrovascular diseases and the failure of perivascular drainage.

Keywords: Alzheimer's disease, artery wall mechanics, cerebral blood flow, cerebral lymphatics

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Authors: Khachen Kongpakwattana, Nathorn Chaiyakunapruk

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Background: Decision-analytic models for Alzheimer’s disease (AD) have been advanced to discrete-event simulation (DES), in which individual-level modelling of disease progression across continuous severity spectra and incorporation of key parameters such as treatment persistence into the model become feasible. This study aimed to apply the DES to perform a cost-effectiveness analysis of treatment for AD in Thailand. Methods: A dataset of Thai patients with AD, representing unique demographic and clinical characteristics, was bootstrapped to generate a baseline cohort of patients. Each patient was cloned and assigned to donepezil, galantamine, rivastigmine, memantine or no treatment. Throughout the simulation period, the model randomly assigned each patient to discrete events including hospital visits, treatment discontinuation and death. Correlated changes in cognitive and behavioral status over time were developed using patient-level data. Treatment effects were obtained from the most recent network meta-analysis. Treatment persistence, mortality and predictive equations for functional status, costs (Thai baht (THB) in 2017) and quality-adjusted life year (QALY) were derived from country-specific real-world data. The time horizon was 10 years, with a discount rate of 3% per annum. Cost-effectiveness was evaluated based on the willingness-to-pay (WTP) threshold of 160,000 THB/QALY gained (4,994 US$/QALY gained) in Thailand. Results: Under a societal perspective, only was the prescription of donepezil to AD patients with all disease-severity levels found to be cost-effective. Compared to untreated patients, although the patients receiving donepezil incurred a discounted additional costs of 2,161 THB, they experienced a discounted gain in QALY of 0.021, resulting in an incremental cost-effectiveness ratio (ICER) of 138,524 THB/QALY (4,062 US$/QALY). Besides, providing early treatment with donepezil to mild AD patients further reduced the ICER to 61,652 THB/QALY (1,808 US$/QALY). However, the dominance of donepezil appeared to wane when delayed treatment was given to a subgroup of moderate and severe AD patients [ICER: 284,388 THB/QALY (8,340 US$/QALY)]. Introduction of a treatment stopping rule when the Mini-Mental State Exam (MMSE) score goes below 10 to a mild AD cohort did not deteriorate the cost-effectiveness of donepezil at the current treatment persistence level. On the other hand, none of the AD medications was cost-effective when being considered under a healthcare perspective. Conclusions: The DES greatly enhances real-world representativeness of decision-analytic models for AD. Under a societal perspective, treatment with donepezil improves patient’s quality of life and is considered cost-effective when used to treat AD patients with all disease-severity levels in Thailand. The optimal treatment benefits are observed when donepezil is prescribed since the early course of AD. With healthcare budget constraints in Thailand, the implementation of donepezil coverage may be most likely possible when being considered starting with mild AD patients, along with the stopping rule introduced.

Keywords: Alzheimer's disease, cost-effectiveness analysis, discrete event simulation, health technology assessment

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Authors: Huan Peng, Chenye Zeng, Zhao Wang

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Alzheimer’s disease (AD) is an age-related neurodegenerative disease that is a leading cause of dementia syndromes and has become a huge burden on society and families. The main pathological features of AD involve excessive deposition of β-amyloid (Aβ) and Tau proteins in the brain, resulting in loss of neurons, expansion of neuroinflammation, and cognitive dysfunction in patients. Researchers have found effective drugs to clear the brain of error-accumulating proteins or to slow the loss of neurons, but their direct administration has key bottlenecks such as single-drug limitation, rapid blood clearance rate, impenetrable blood-brain barrier (BBB), and poor ability to target tissues and cells. Therefore, we are committed to seeking a suitable and efficient delivery system. Inspired by the possibility that exosomes may be involved in the secretion and transport mechanism of many signaling molecules or proteins in the brain, exosomes have attracted extensive attention as natural nanoscale drug carriers. We selected exosomes derived from bone marrow mesenchymal stem cells (MSC-EXO) with low immunogenicity and exosomes derived from hippocampal neurons (HT22-EXO) that may have excellent homing ability to overcome the deficiencies of oral or injectable pathways and bypass the BBB through nasal administration and evaluated their delivery ability and effect on AD. First, MSC-EXO and HT22 cells were isolated and cultured, and MSCs were identified by microimaging and flow cytometry. Then MSC-EXO and HT22-EXO were obtained by gradient centrifugation and qEV SEC separation column, and a series of physicochemical characterization were performed by transmission electron microscope, western blot, nanoparticle tracking analysis and dynamic light scattering. Next, exosomes labeled with lipophilic fluorescent dye were administered to WT mice and APP/PS1 mice to obtain fluorescence images of various organs at different times. Finally, APP/PS1 mice were administered intranasally with two exosomes 20 times over 40 days and 20 μL each time. Behavioral analysis and pathological section analysis of the hippocampus were performed after the experiment. The results showed that MSC-EXO and HT22-EXO were successfully isolated and characterized, and they had good biocompatibility. MSC-EXO showed excellent brain enrichment in APP/PS1 mice after intranasal administration, could improve the neuronal damage and reduce inflammation levels in the hippocampus of APP/PS1 mice, and the improvement effect was significantly better than HT22-EXO. However, intranasal administration of the two exosomes did not cause depression and anxious-like phenotypes in APP/PS1 mice, nor significantly improved the short-term or spatial learning and memory ability of APP/PS1 mice, and had no significant effect on the content of Aβ plaques in the hippocampus, which also meant that MSC-EXO could use their own advantages in combination with other drugs to clear Aβ plaques. The possibility of realizing highly effective non-invasive synergistic treatment for AD provides new strategies and ideas for clinical research.

Keywords: Alzheimer’s disease, exosomes derived from mesenchymal stem cell, intranasal administration, therapy-carrier dual roles

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Authors: Cornelia-Eugenia Munteanu

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The goal of this paper is to present the diagnostic contribution that the screening instrument, Mini-Mental State Examination-2: Expanded Version (MMSE-2:EV), brings in detecting the cognitive impairment or in monitoring the progress of degenerative disorders. The diagnostic signification is underlined by the interpretation of the MMSE-2:EV scores, resulted from the test application to patients with mild and major neurocognitive disorders. The original MMSE is one of the most widely used screening tools for detecting the cognitive impairment, in clinical settings, but also in the field of neurocognitive research. Now, the practitioners and researchers are turning their attention to the MMSE-2. To enhance its clinical utility, the new instrument was enriched and reorganized in three versions (MMSE-2:BV, MMSE-2:SV and MMSE-2:EV), each with two forms: blue and red. The MMSE-2 was adapted and used successfully in Romania since 2013. The cases were selected from current practice, in order to cover vast and significant neurocognitive pathology: mild cognitive impairment, Alzheimer’s disease, vascular dementia, mixed dementia, Parkinson’s disease, conversion of the mild cognitive impairment into Alzheimer’s disease. The MMSE-2:EV version was used: it was applied one month after the initial assessment, three months after the first reevaluation and then every six months, alternating the blue and red forms. Correlated with age and educational level, the raw scores were converted in T scores and then, with the mean and the standard deviation, the z scores were calculated. The differences of raw scores between the evaluations were analyzed from the point of view of statistic signification, in order to establish the progression in time of the disease. The results indicated that the psycho-diagnostic approach for the evaluation of the cognitive impairment with MMSE-2:EV is safe and the application interval is optimal. The alternation of the forms prevents the learning phenomenon. The diagnostic accuracy and efficient therapeutic conduct derive from the usage of the national test norms. In clinical settings with a large flux of patients, the application of the MMSE-2:EV is a safe and fast psycho-diagnostic solution. The clinicians can draw objective decisions and for the patients: it doesn’t take too much time and energy, it doesn’t bother them and it doesn’t force them to travel frequently.

Keywords: MMSE-2, dementia, cognitive impairment, neuropsychology

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Authors: Lise Paesen, Marielle Leijten

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People diagnosed with probable Alzheimer disease suffer from an impairment of their language capacities; a gradual impairment which affects both their spoken and written communication. Our study aims at characterising the language decline in DAT patients with the use of congeneric elicited writing tasks. Within these tasks, a descriptive text has to be written based upon images with which the participants are confronted. A randomised set of images allows us to present the participants with a different task on every encounter, thus allowing us to avoid a recognition effect in this iterative study. This method is a revision from previous studies, in which participants were presented with a larger picture depicting an entire scene. In order to create the randomised set of images, existing pictures were adapted following strict criteria (e.g. frequency, AoA, colour, ...). The resulting data set contained 50 images, belonging to several categories (vehicles, animals, humans, and objects). A pre-test was constructed to validate the created picture set; most images had been used before in spoken picture naming tasks. Hence the same reaction times ought to be triggered in the typed picture naming task. Once validated, the effectiveness of the descriptive tasks was assessed. First, the participants (n=60 students, n=40 healthy elderly) performed a typing task, which provided information about the typing speed of each individual. Secondly, two descriptive writing tasks were carried out, one simple and one complex. The simple task contains 4 images (1 animal, 2 objects, 1 vehicle) and only contains elements with high frequency, a young AoA (<6 years), and fast reaction times. Slow reaction times, a later AoA (≥ 6 years) and low frequency were criteria for the complex task. This task uses 6 images (2 animals, 1 human, 2 objects and 1 vehicle). The data were collected with the keystroke logging programme Inputlog. Keystroke logging tools log and time stamp keystroke activity to reconstruct and describe text production processes. The data were analysed using a selection of writing process and product variables, such as general writing process measures, detailed pause analysis, linguistic analysis, and text length. As a covariate, the intrapersonal interkey transition times from the typing task were taken into account. The pre-test indicated that the new images lead to similar or even faster reaction times compared to the original images. All the images were therefore used in the main study. The produced texts of the description tasks were significantly longer compared to previous studies, providing sufficient text and process data for analyses. Preliminary analysis shows that the amount of words produced differed significantly between the healthy elderly and the students, as did the mean length of production bursts, even though both groups needed the same time to produce their texts. However, the elderly took significantly more time to produce the complex task than the simple task. Nevertheless, the amount of words per minute remained comparable between simple and complex. The pauses within and before words varied, even when taking personal typing abilities (obtained by the typing task) into account.

Keywords: Alzheimer's disease, experimental design, language decline, writing process

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Authors: Majed Al Otaibi, Melissa Lessard-Beaudoin, Amel Loudghi, Raphael Chouinard-Watkins, Melanie Plourde, Frederic Calon, C. Alexandre Castellano, Stephen Cunnane, Helene Payette, Pierrette Gaudreau, Denis Gris, Rona K. Graham

Abstract:

Introduction: Alzheimer disease (AD) is a chronic disorder that affects millions of individuals worldwide. Symptoms include memory dysfunction, and also alterations in attention, planning, language and overall cognitive function. Olfactory dysfunction is a common symptom of several neurological disorders including AD. Studying the mechanisms underlying the olfactory dysfunction may therefore lead to the discovery of potential biomarkers and/or treatments for neurodegenerative diseases. Objectives: To determine if olfactory dysfunction predicts future cognitive impairment in the aging population and to characterize the olfactory system in a murine model expressing a genetic factor of AD. Method: For the human study, quantitative olfactory tests (UPSIT and OMT) have been done on 93 subjects (aged 80 to 94 years) from the Quebec Longitudinal Study on Nutrition and Successful Aging (NuAge) cohort accepting to participate in the ORCA secondary study. The telephone Modified Mini Mental State examination (t-MMSE) was used to assess cognition levels, and an olfactory self-report was also collected. In a separate cohort, olfactory cortical volume was calculated using MRI results from healthy old adults (n=25) and patients with AD (n=18) using the AAL single-subject atlas and performed with the PNEURO tool (PMOD 3.7). For the murine study, we are using Western blotting, RT-PCR and immunohistochemistry. Result: Human Study: Based on the self-report, 81% of the participants claimed to not suffer from any problem with olfaction. However, based on the UPSIT, 94% of those subjects showed a poor olfactory performance and different forms of microsmia. Moreover, the results confirm that olfactory function declines with age. We also detected a significant decrease in olfactory cortical volume in AD individuals compared to controls. Murine study: Preliminary data demonstrate there is a significant decrease in expression levels of the proform of caspase-3 and the caspase substrate STK3, in the olfactory bulb of mice expressing human APOE4 compared with controls. In addition, there is a significant decrease in the expression level of the caspase-9 proform and caspase-8 active fragment. Analysis of the mature neuron marker, NeuN, shows decreased expression levels of both isoforms. The data also suggest that Iba-1 immunostaining is increased in the olfactory bulb of APOE4 mice compared to wild type mice. Conclusions: The activation of caspase-3 may be the cause of the decreased levels of STK3 through caspase cleavage and may play role in the inflammation observed. In the clinical study, our results suggest that seniors are unaware of their olfactory function status and therefore it is not sufficient to measure olfaction using the self-report in the elderly. Studying olfactory function and cognitive performance in the aging population will help to discover biomarkers in the early stage of the AD.

Keywords: Alzheimer's disease, APOE4, cognition, caspase, brain atrophy, neurodegenerative, olfactory dysfunction

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Authors: Merve Colak, Gizem Donmez Yalcin

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Glutamate has many neurological functions in the central nervous system and is found at high concentrations in the brain. Increased levels of glutamate in the neuronal space are toxic, causing neuron damage and death. This is called glutamate-induced excitotoxicity. Excitotoxicity is among the causes of many neurological diseases such as trauma, cerebral ischemia, epilepsy, Parkinson's Disease, Alzheimer's Disease. Since neuroblastoma cells are known to be excitotoxic, we propose that excitotoxicity can be studied in neuroblastoma cells. Excitotoxicity can be induced using kainic acid in neuroblastoma cells. Measuring the secretion of glutamate, excitotoxicity can be analyzed in neuroblastoma cells.

Keywords: glutamate, excitotoxicity, kainic acid, Sirt4

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Authors: Marielle Leijten, Catherine Meulemans, Sven De Maeyer, Luuk Van Waes

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For the diagnosis of Alzheimer's disease (AD), a large variety of neuropsychological tests are available. In some of these tests, linguistic processing - both oral and written - is an important factor. Language disturbances might serve as a strong indicator for an underlying neurodegenerative disorder like AD. However, the current diagnostic instruments for language assessment mainly focus on product measures, such as text length or number of errors, ignoring the importance of the process that leads to written or spoken language production. In this study, it is our aim to describe and test differences between cognitive and impaired elderly on the basis of a selection of writing process variables (inter- and intrapersonal characteristics). These process variables are mainly related to pause times, because the number, length, and location of pauses have proven to be an important indicator of the cognitive complexity of a process. Method: Participants that were enrolled in our research were chosen on the basis of a number of basic criteria necessary to collect reliable writing process data. Furthermore, we opted to match the thirteen cognitively impaired patients (8 MCI and 5 AD) with thirteen cognitively healthy elderly. At the start of the experiment, participants were each given a number of tests, such as the Mini-Mental State Examination test (MMSE), the Geriatric Depression Scale (GDS), the forward and backward digit span and the Edinburgh Handedness Inventory (EHI). Also, a questionnaire was used to collect socio-demographic information (age, gender, eduction) of the subjects as well as more details on their level of computer literacy. The tests and questionnaire were followed by two typing tasks and two picture description tasks. For the typing tasks participants had to copy (type) characters, words and sentences from a screen, whereas the picture description tasks each consisted of an image they had to describe in a few sentences. Both the typing and the picture description tasks were logged with Inputlog, a keystroke logging tool that allows us to log and time stamp keystroke activity to reconstruct and describe text production processes. The main rationale behind keystroke logging is that writing fluency and flow reveal traces of the underlying cognitive processes. This explains the analytical focus on pause (length, number, distribution, location, etc.) and revision (number, type, operation, embeddedness, location, etc.) characteristics. As in speech, pause times are seen as indexical of cognitive effort. Results. Preliminary analysis already showed some promising results concerning pause times before, within and after words. For all variables, mixed effects models were used that included participants as a random effect and MMSE scores, GDS scores and word categories (such as determiners and nouns) as a fixed effect. For pause times before and after words cognitively impaired patients paused longer than healthy elderly. These variables did not show an interaction effect between the group participants (cognitively impaired or healthy elderly) belonged to and word categories. However, pause times within words did show an interaction effect, which indicates pause times within certain word categories differ significantly between patients and healthy elderly.

Keywords: Alzheimer's disease, keystroke logging, matching, writing process

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Authors: Leila Keshavarz Afshar, Hedieh Sajedi

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Estimation of biological brain age from MR images is a topic that has been much addressed in recent years due to the importance it attaches to early diagnosis of diseases such as Alzheimer's. In this paper, we use a 3D Convolutional Neural Network (CNN) to provide a method for estimating the biological age of the brain. The 3D-CNN model is trained by MRI data that has been normalized. In addition, to reduce computation while saving overall performance, some effectual slices are selected for age estimation. By this method, the biological age of individuals using selected normalized data was estimated with Mean Absolute Error (MAE) of 4.82 years.

Keywords: brain age estimation, biological age, 3D-CNN, deep learning, T1-weighted image, SPM, preprocessing, MRI, canny, gray matter

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Authors: Felicia N. Obialo, Aliza Wingo, Thomas Wingo

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Psychosocial factors such as personality traits and social networks influence cognitive aging and dementia outcomes both positively and negatively. The inherent complexity of these factors makes defining the underlying mechanisms of their influence difficult; however, exploring their interactions affords promise in the field of cognitive aging. The objective of this study was to elucidate some of these interactions by determining the relationship between social network size and dementia outcomes and by determining whether personality traits mediate this relationship. The longitudinal Alzheimer’s Disease (AD) database provided by Rush University’s Religious Orders Study/Memory and Aging Project was utilized to perform retrospective regression and mediation analyses on 3,591 participants. Participants who were cognitively impaired at baseline were excluded, and analyses were adjusted for age, sex, common chronic diseases, and vascular risk factors. Dementia outcome measures included cognitive trajectory, clinical dementia diagnosis, and postmortem beta-amyloid plaque (AB), and neurofibrillary tangle (NT) accumulation. Personality traits included agreeableness (A), conscientiousness (C), extraversion (E), neuroticism (N), and openness (O). The results show a positive correlation between social network size and cognitive trajectory (p-value = 0.004) and a negative relationship between social network size and odds of dementia diagnosis (p = 0.024/ Odds Ratio (OR) = 0.974). Only neuroticism mediates the positive relationship between social network size and cognitive trajectory (p < 2e-16). Agreeableness, extraversion, and neuroticism all mediate the negative relationship between social network size and dementia diagnosis (p=0.098, p=0.054, and p < 2e-16, respectively). All personality traits are independently associated with dementia diagnosis (A: p = 0.016/ OR = 0.959; C: p = 0.000007/ OR = 0.945; E: p = 0.028/ OR = 0.961; N: p = 0.000019/ OR = 1.036; O: p = 0.027/ OR = 0.972). Only conscientiousness and neuroticism are associated with postmortem AD pathologies; specifically, conscientiousness is negatively associated (AB: p = 0.001, NT: p = 0.025) and neuroticism is positively associated with pathologies (AB: p = 0.002, NT: p = 0.002). These results support the study’s objectives, demonstrating that social network size and personality traits are strongly associated with dementia outcomes, particularly the odds of receiving a clinical diagnosis of dementia. Personality traits interact significantly and beneficially with social network size to influence the cognitive trajectory and future dementia diagnosis. These results reinforce previous literature linking social network size to dementia risk and provide novel insight into the differential roles of individual personality traits in cognitive protection.

Keywords: Alzheimer’s disease, cognitive trajectory, personality traits, social network size

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Authors: Michael Joseph Passmore

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Euthanasia, or assisted suicide (EAS), refers to the provision of medical assistance to individuals seeking to end their own lives. In Canada, the issue of EAS has been the subject of debate and legislative action for many years. In 2016, the Canadian government passed the Medical Assistance in Dying (MAID) Act. This legalized EAS in Canada is subject to certain eligibility criteria. In 2023, debate in Canada continues regarding the scope of MAID practice and associated legislation. Dementia is an illness that causes suffering at the end of life. Persons suffering due to dementia deserve timely and effective palliative care.

Keywords: palliative care, neurocognitive disorder, dementia, Alzheimer’s disease, euthanasia, assisted suicide, medical ethics, bioethics

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Authors: Yung-Chih Kuo, Che-Yu Lin, Jay-Shake Li, Yung-I Lou

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Curcumin (CRM) and nerve growth factor (NGF) were entrapped in liposomes (LIP) with cardiolipin (CL) to downregulate the phosphorylation of mitogen-activated protein kinases for Alzheimer’s disease (AD) management. AD belongs to neurodegenerative disorder with a gradual loss of memory, yielding irreversible dementia. CL-conjugated LIP loaded with CRM (CRM-CL/LIP) and that with NGF (NGF-CL/LIP) were applied to AD models of SK-N-MC cells and Wistar rats with an insult of β-amyloid peptide (Aβ). Lipids comprising 1,2-dipalmitoyl-sn-glycero-3- phosphocholine (Avanti Polar Lipids, Alabaster, AL), 1',3'-bis[1,2- dimyristoyl-sn-glycero-3-phospho]-sn-glycerol (CL; Avanti Polar Lipids), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-2000] (Avanti Polar Lipids), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000] (Avanti Polar Lipids) and CRM (Sigma–Aldrich, St. Louis, MO) were dissolved in chloroform (J. T. Baker, Phillipsburg, NJ) and condensed using a rotary evaporator (Panchum, Kaohsiung, Taiwan). Human β-NGF (Alomone Lab, Jerusalem, Israel) was added in the aqueous phase. Wheat germ agglutinin (WGA; Medicago AB, Uppsala, Sweden) was grafted on LIP loaded with CRM for (WGA-CRM-LIP) and CL-conjugated LIP loaded with CRM (WGA-CRM-CL/LIP) using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (Sigma–Aldrich) and N-hydroxysuccinimide (Alfa Aesar, Ward Hill, MA). The protein samples of SK-N-MC cells (American Type Tissue Collection, Rockville, MD) were used for sodium dodecyl sulfate (Sigma–Aldrich) polyacrylamide gel (Sigma–Aldrich) electrophoresis. In animal study, the LIP formulations were administered by intravenous injection via a tail vein of male Wistar rats (250–280 g, 8 weeks, BioLasco, Taipei, Taiwan), which were housed in the Animal Laboratory of National Chung Cheng University in accordance with the institutional guidelines and the guidelines of Animal Protection Committee under the Council of Agriculture of the Republic of China. We found that CRM-CL/LIP could inhibit the expressions of phosphorylated p38 (p-p38), p-Jun N-terminal kinase (p-JNK), and p-tau protein at serine 202 (p-Ser202) to retard the neuronal apoptosis. Free CRM and released CRM from CRM-LIP and CRM-CL/LIP were not in a straightforward manner to effectively inhibit the expression of p-p38 and p-JNK in the cytoplasm. In addition, NGF-CL/LIP enhanced the quantities of p-neurotrophic tyrosine kinase receptor type 1 (p-TrkA) and p-extracellular-signal-regulated kinase 5 (p-ERK5), preventing the Aβ-induced degeneration of neurons. The membrane fusion of NGF-LIP activated the ERK5 pathway and the targeting capacity of NGF-CL/LIP enhanced the possibility of released NGF to affect the TrkA level. Moreover, WGA-CRM-LIP improved the permeation of CRM across the blood–brain barrier (BBB) and significantly reduced the Aβ plaque deposition and malondialdehyde level and increased the percentage of normal neurons and cholinergic function in the hippocampus of AD rats. This was mainly because the encapsulated CRM was protected by LIP against a rapid degradation in the blood. Furthermore, WGA on LIP could target N-acetylglucosamine on endothelia and increased the quantity of CRM transported across the BBB. In addition, WGA-CRM-CL/LIP could be effective in suppressing the synthesis of acetylcholinesterase and reduced the decomposition of acetylcholine for better neurotransmission. Based on the in vitro and in vivo evidences, WGA-CRM-CL/LIP can rescue neurons from apoptosis in the brain and can be a promising drug delivery system for clinical AD therapy.

Keywords: Alzheimer’s disease, β-amyloid, liposome, mitogen-activated protein kinase

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Authors: Rachel Matar, Maxime Merheb

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Chemical drugs have been used for many centuries as the only way to cure diseases until the novel gene therapy has been created in 1960. Gene therapy is based on the insertion, correction, or inactivation of genes to treat people with genetic illness (1). Gene therapy has made wonders in Parkison’s, Alzheimer and multiple sclerosis. In addition to great promises in the healing of deadly diseases like many types of cancer and autoimmune diseases (2). This method implies the use of recombinant DNA technology with the help of different viral and non-viral vectors (3). It is nowadays used in somatic cells as well as embryos and gametes. Beside all the benefits of gene therapy, this technique is deemed by some opponents as an ethically unacceptable treatment as it implies playing with the genes of living organisms.

Keywords: gene therapy, genetic disease, cancer, multiple sclerosis

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Authors: Fatih Sonmez

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease and it is the most common form of dementia that affects aged people. Acetylcholinesterase is a hydrolase involved in the termination of impulse transmission at cholinergic synapses by rapid hydrolysis of the neurotransmitter ACh in the central and peripheral nervous system. Carvacrol (5-iso-propyl-2-methyl-phenol) is a main bioactive monoterpene isolated from many medicinal herbs, such as Thymus vulgaris, Monarda punctate and Origanum vulgare spp. It is known that carvacrol has been widely used as an active anti-inflammatory ingredient, which can inhibit the isoproterenol induced inflammation in myocardial infarcted rats. In this paper, a series of 12 carvacrol substituted carbamate derivatives (2a-l) was synthesized and their inhibitory activities on AChE and BuChE were evaluated. Among them, 2d exhibited the strongest inhibition against AChE with an IC50 value of 2.22 µM, which was 130-fold more than that of carvacrol (IC50 = 288.26 µM).

Keywords: Acetylcholinesterase, Butyrylcholinesterase, Carbamate, Carvacrol

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Authors: Santiago Quesada-García, María Lozano-Gómez, Pablo Valero-Flores

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The recent digital revolution, together with modern technologies, is changing the environment and the way people interact with inhabited space. However, in society, the elderly are a very broad and varied group that presents serious difficulties in understanding these modern technologies. Outpatients with cognitive disabilities, such as those suffering from Alzheimer's disease (AD), are distinguished within this cluster. This population group is in constant growth, and they have specific requirements for their inhabited space. According to architecture, which is one of the health humanities, environments are designed to promote well-being and improve the quality of life for all. Buildings, as well as the tools and technologies integrated into them, must be accessible, inclusive, and foster health. In this new digital paradigm, artificial intelligence (AI) appears as an innovative resource to help this population group improve their autonomy and quality of life. Some experiences and solutions, such as those that interact with users through chatbots and voicebots, show the potential of AI in its practical application. In the design of healthy spaces, the integration of AI in architecture will allow the living environment to become a kind of 'exo-brain' that can make up for certain cognitive deficiencies in this population. The objective of this paper is to address, from the discipline of neuroarchitecture, how modern technologies can be integrated into everyday environments and be an accessible resource for people with cognitive disabilities. For this, the methodology has a mixed structure. On the one hand, from an empirical point of view, the research carries out a review of the existing literature about the applications of AI to build space, following the critical review foundations. As a unconventional architectural research, an experimental analysis is proposed based on people with AD as a resource of data to study how the environment in which they live influences their regular activities. The results presented in this communication are part of the progress achieved in the competitive R&D&I project ALZARQ (PID2020-115790RB-I00). These outcomes are aimed at the specific needs of people with cognitive disabilities, especially those with AD, since, due to the comfort and wellness that the solutions entail, they can also be extrapolated to the whole society. As a provisional conclusion, it can be stated that, in the immediate future, AI will be an essential element in the design and construction of healthy new environments. The discipline of architecture has the compositional resources to, through this emerging technology, build an 'exo-brain' capable of becoming a personal assistant for the inhabitants, with whom to interact proactively and contribute to their general well-being. The main objective of this work is to show how this is possible.

Keywords: Alzheimer’s disease, artificial intelligence, healthy architecture, neuroarchitecture, architectural design

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Authors: Hardeep

Abstract:

The aim of this research work to improve the solubility and bioavailability of Simvastatin using a self nanoemulsifying drug delivery system (SNEDDS). Self emulsifying property of various oils including essential oils was evaluated with suitable surfactants and co-surfactants. Validation of a method for accuracy, repeatability, Interday and intraday precision, ruggedness, and robustness were within acceptable limits. The liquid SNEDDS was prepared and optimized using a ternary phase diagram, thermodynamic, centrifugation and cloud point studies. The globule size of optimized formulations was less than 200 nm which could be an acceptable nanoemulsion size range. The mean droplet size, drug loading, PDI and zeta potential were found to be 141.0 nm, 92.22%, 0.23 and -10.13 mV and 153.5nm, 93.89 % ,0.41 and -11.7 mV and 164.26 nm, 95.26% , 0.41 and -10.66mV respectively.

Keywords: simvastatin, self nanoemulsifying drug delivery system, solubility, bioavailability

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Authors: Angela T. H. Kwan, Saman Arfaie, Joseph Therriault, Zahra Azizi, Firoza Z. Lussier, Cecile Tissot, Mira Chamoun, Gleb Bezgin, Stijn Servaes, Jenna Stevenon, Nesrine Rahmouni, Vanessa Pallen, Serge Gauthier, Pedro Rosa-Neto

Abstract:

Alzheimer’s disease (AD) can be detected in living people using in vivo biomarkers of amyloid-β (Aβ) and tau, even in the absence of cognitive impairment during the preclinical phase. [¹⁸F]-MK-6420 is a high affinity positron emission tomography (PET) tracer that quantifies tau neurofibrillary tangles, but its ability to predict cognitive changes associated with early AD symptoms, such as memory decline, is unclear. Here, we assess the prognostic accuracy of baseline [18F]-MK-6420 tau PET for predicting longitudinal memory decline in asymptomatic elderly individuals. In a longitudinal observational study, we evaluated a cohort of cognitively normal elderly participants (n = 111) from the Translational Biomarkers in Aging and Dementia (TRIAD) study (data collected between October 2017 and July 2020, with a follow-up period of 12 months). All participants underwent tau PET with [¹⁸F]-MK-6420 and Aβ PET with [¹⁸F]-AZD-4694. The exclusion criteria included the presence of head trauma, stroke, or other neurological disorders. There were 111 eligible participants who were chosen based on the availability of Aβ PET, tau PET, magnetic resonance imaging (MRI), and APOEε4 genotyping. Among these participants, the mean (SD) age was 70.1 (8.6) years; 20 (18%) were tau PET positive, and 71 of 111 (63.9%) were women. A significant association between baseline Braak I-II [¹⁸F]-MK-6240 SUVR positivity and change in composite memory score was observed at the 12-month follow-up, after correcting for age, sex, and years of education (Logical Memory and RAVLT, standardized beta = -0.52 (-0.82-0.21), p < 0.001, for dichotomized tau PET and -1.22 (-1.84-(-0.61)), p < 0.0001, for continuous tau PET). Moderate cognitive decline was observed for A+T+ over the follow-up period, whereas no significant change was observed for A-T+, A+T-, and A-T-, though it should be noted that the A-T+ group was small.Our results indicate that baseline tau neurofibrillary tangle pathology is associated with longitudinal changes in memory function, supporting the use of [¹⁸F]-MK-6420 PET to predict the likelihood of asymptomatic elderly individuals experiencing future memory decline. Overall, [¹⁸F]-MK-6420 PET is a promising tool for predicting memory decline in older adults without cognitive impairment at baseline. This is of critical relevance as the field is shifting towards a biological model of AD defined by the aggregation of pathologic tau. Therefore, early detection of tau pathology using [¹⁸F]-MK-6420 PET provides us with the hope that living patients with AD may be diagnosed during the preclinical phase before it is too late.

Keywords: alzheimer’s disease, braak I-II, in vivo biomarkers, memory, PET, tau

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Authors: Gokhan Zengin, Abdurrahman Aktumsek

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The key enzyme inhibitory theory is one of the most accepted strategies in the treatment of global health problems including Alzheimer’s Disease and Diabetes mellitus. For this reason, the enzyme inhibitory potentials of different solvent extracts from Linaria genistifolia subsp. genistifolia were investigated against cholinesterase, and tyrosinase. The in vitro enzyme inhibitory potentials were measured with a microplate reader. The acetone and methanol extracts exhibited the strongest enzyme inhibitory effects on cholinesterase. However, the water extract was only active on tyrosinase. The results suggested that Linaria genistifolia subsp. genistifolia could be considered as a source of natural enzyme inhibitors for the treatment of major health problems.

Keywords: enzyme inhibitors, cholinesterase, tyrosinase, linaria, Turkey

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Authors: Zoi Konsoula

Abstract:

The increasing prevalence of Alzheimer’s disease (AD) and diabetes mellitus (DM) constitutes them major global health problems. Recently, the inhibition of key enzyme activity is considered a potential treatment of both diseases. Specifically, inhibition of acetylcholinesterase (AChE), the key enzyme involved in the breakdown of the neurotransmitter acetylcholine, is a promising approach for the treatment of AD, while inhibition of α-amylase retards the hydrolysis of carbohydrates and, thus, reduces hyperglycemia. Unfortunately, commercially available AChE and α-amylase inhibitors are reported to possess side effects. Consequently, there is a need to develop safe and effective treatments for both diseases. In the present study, pomegranate peel (PP) was extracted using various solvents of increasing polarity, while two extraction methods were employed, the conventional maceration and the ultrasound assisted extraction (UAE). The concentration of bioactive phytoconstituents, such as total phenolics (TPC) and total flavonoids (TFC) in the prepared extracts was evaluated by the Folin-Ciocalteu and the aluminum-flavonoid complex method, respectively. Furthermore, the anti-neurodegenerative and anti-hyperglycemic activity of all extracts was determined using AChE and α-amylase inhibitory activity assays, respectively. The inhibitory activity of the extracts against AChE and α-amylase was characterized by estimating their IC₅₀ value using a dose-response curve, while galanthamine and acarbose were used as positive controls, respectively. Finally, the kinetics of AChE and α-amylase in the presence of the most inhibitory potent extracts was determined by the Lineweaver-Burk plot. The methanolic extract prepared using the UAE contained the highest amount of phytoconstituents, followed by the respective ethanolic extract. All extracts inhibited acetylcholinesterase in a dose-dependent manner, while the increased anticholinesterase activity of the methanolic (IC₅₀ = 32 μg/mL) and ethanolic (IC₅₀ = 42 μg/mL) extract was positively correlated with their TPC content. Furthermore, the activity of the aforementioned extracts was comparable to galanthamine. Similar results were obtained in the case of α-amylase, however, all extracts showed lower inhibitory effect on the carbohydrate hydrolyzing enzyme than on AChE, since the IC₅₀ value ranged from 84 to 100 μg/mL. Also, the α-amylase inhibitory effect of the extracts was lower than acarbose. Finally, the methanolic and ethanolic extracts prepared by UAE inhibited both enzymes in a mixed (competitive/noncompetitive) manner since the Kₘ value of both enzymes increased in the presence of extracts, while the Vmax value decreased. The results of the present study indicate that PP may be a useful source of active compounds for the management of AD and DM. Moreover, taking into consideration that PP is an agro-industrial waste product, its valorization could not only result in economic efficiency but also reduce the environmental pollution.

Keywords: acetylcholinesterase, Alzheimer’s disease, α-amylase, diabetes mellitus, pomegranate

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Authors: Ramazan Bakir, Gizem Kayar

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It is known that Alzheimer and Dementia are the two most common types of Neurodegenerative diseases and their visibility is getting accelerated for the last couple of years. As the population sees older ages all over the world, researchers expect to see the rate of this acceleration much higher. However, unfortunately, there is no known pharmacological cure for both, although some help to reduce the rate of cognitive decline speed. This is why we encounter with non-pharmacological treatment and tracking methods more for the last five years. Many researchers, including well-known associations and hospitals, lean towards using non-pharmacological methods to support cognitive function and improve the patient’s life quality. As the dementia symptoms related to mind, learning, memory, speaking, problem-solving, social abilities and daily activities gradually worsen over the years, many researchers know that cognitive support should start from the very beginning of the symptoms in order to slow down the decline. At this point, life of a patient and caregiver can be improved with some daily activities and applications. These activities include but not limited to basic word puzzles, daily cleaning activities, taking notes. Later, these activities and their results should be observed carefully and it is only possible during patient/caregiver and M.D. in-person meetings in hospitals. These meetings can be quite time-consuming, exhausting and financially ineffective for hospitals, medical doctors, caregivers and especially for patients. On the other hand, digital support systems are showing positive results for all stakeholders of healthcare systems. This can be observed in countries that started Telemedicine systems. The biggest potential of our system is setting the inter-user communication up in the best possible way. In our project, we propose Machine Learning based digitalization of validated traditional cognitive tests (e.g. MOCA, Afazi, left-right hemisphere), their analyses for high-quality follow-up and communication systems for all stakeholders. R. Bakir and G. Kayar are with Gefeasoft, Inc, R&D – Software Development and Health Technologies company. Emails: ramazan, gizem @ gefeasoft.com This platform has a high potential not only for patient tracking but also for making all stakeholders feel safe through all stages. As the registered hospitals assign corresponding medical doctors to the system, these MDs are able to register their own patients and assign special tasks for each patient. With our integrated machine learning support, MDs are able to track the failure and success rates of each patient and also see general averages among similarly progressed patients. In addition, our platform also supports multi-player technology which helps patients play with their caregivers so that they feel much safer at any point they are uncomfortable. By also gamifying the daily household activities, the patients will be able to repeat their social tasks and we will provide non-pharmacological reminiscence therapy (RT – life review therapy). All collected data will be mined by our data scientists and analyzed meaningfully. In addition, we will also add gamification modules for caregivers based on Naomi Feil’s Validation Therapy. Both are behaving positively to the patient and keeping yourself mentally healthy is important for caregivers. We aim to provide a therapy system based on gamification for them, too. When this project accomplishes all the above-written tasks, patients will have the chance to do many tasks at home remotely and MDs will be able to follow them up very effectively. We propose a complete platform and the whole project is both time and cost-effective for supporting all stakeholders.

Keywords: alzheimer’s, dementia, cognitive functionality, cognitive tests, serious games, machine learning, artificial intelligence, digitalization, non-pharmacological, data analysis, telemedicine, e-health, health-tech, gamification

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Authors: Hassina Harkat, Samiha Taybe, Salima Loucif, Valérie Beneteau, Patrick Pale

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Indole and its derivatives have attracted great interest because of their importance in the synthetic organic and medicinal chemistry. They are widely used as anti hypertension, anti tubercular, anticancer activity, antiviral, Alzheimer's disease, antioxidant properties, and free radical induced lipid peroxidation. Many drugs and natural products contain indole moiety, such as the vinca alkaloids, fungal metabolites and marine natural products. Generally applicable synthetic methods for indole moiety involve ring closure to form the pyrrole. Indole derivatives can also be accessed by further functionalization of the indole nucleus. Therefore we report a mild and efficient protocol for the synthesis of analogues of indole catalyzed via zeolithe USY doped with CuI under solvent-free conditions.

Keywords: indole, zeolithe, USY-CuI, heterogeneous catalysis

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Authors: Garima Joshi, Ashima N. Wadhawan

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Neuropsychology in India is a fairly new field, having started only four decades back. Neuropsychology has come a long way since the establishment of the first department, from using western batteries for assessing patients to the development of highly reliable indigenous tools for assessing neuropsychological functioning. Clinical neuropsychology has risen as a discipline in the field of assessing and rehabilitating patients with various neurological conditions such as Traumatic Brain Injury, Stroke, Mild Cognitive Impairment, Alzheimer’s, Schizophrenia and other disorders with cognitive decline. The current review attempts to assimilate the history of the discipline in India, along with the current developments and future direction of the field and highlights the pursuit and undertakings of the scientists to provide culturally appropriate services, in terms of assessment and rehabilitation, to the Indian population.

Keywords: clinical neuropsychology, cognitive assessment, cognitive rehabilitation, neuropsychological test batteries in India

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Authors: Agnieszka Fryźlewicz, Jowita Kras, Mikołaj Sadowski, Agnieszka Łapczuk-Krygier, Agnieszka Kącka-Zych Radomir Jasiński

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Nicotines are a group of compounds containing conjugated pyridine and pyrrolidine molecular segments. They are widely applied in medicine, pharmacy, and agriculture. Namely as researched treatment of Alzheimer, depression, Parkinson's, Tourette syndrome, general nervous and mental disorders. Furthermore, nicotine itself is used as a stimulant, animal repellent and was widely applied as an insecticide. In our work, we obtained nicotine analogues with possible applications in agriculture. The synthesis employed [3+2] cycloaddition (32CA) reactions, occurring between pirydyl-functionalised nitrones and conjugated nitroalkenes, that allowed us to fully regio- and stereoselectively obtain product. Moreover, cycloaddition reaction realizes rapidly in mild conditions with the full atomic economy, thus fitting into “green chemistry” trends.

Keywords: nicotine, isoxazolidine, 1-3-dipolar cycloaddition, green chemistry, biological and pharmacological activity

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Authors: Ragu Sasikumar, Palraj Ranganathan, Shen-Ming Chen, Syang-Peng Rwei

Abstract:

A highly sensitive, and selective α-Lipoic acid (ALA) sensor based on a functionalized multi-walled carbon nanotubes-polyindole/Ti2O3 (f-MWCNTs-PIN/Ti2O3) nanocomposite modified glassy carbon electrode (GCE) was developed. The fabricated f-MWCNTs-PIN/Ti2O3/GCE displayed an enhanced voltammetric response for oxidation towards ALA relative to that of a f-MWCNTs/GCE, f-MWCNTs-PIN/GCE, Ti2O3/GCE, and a bare GCE. Under optimum conditions, the f-MWCNTs-PIN/Ti2O3/GCE showed a wide linear range at ALA concentrations of 0.39-115.8 µM. The limit of detection of 12 nM and sensitivity of about 6.39 µA µM-1cm-2. The developed sensor showed anti-interference, reproducibility, good repeatability, and operational stability. Applied possibility of the sensor has been confirmed in vegetable samples.

Keywords: f-MWCNT, polyindole, Ti2O3, Alzheimer’s diseases, ALA sensor

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